Evidentia September 2011 by Peter Mas-Mollinedo

Volume 5 Issue 4 | August/September 2011 | ISSN 1753-464X

Athletes need early diagnosis and treatment of skin infections

Teens with cancer facing unique challenges Dentists could identify undiagnosed diabetes Compounds found in tree can fight MRSA Mobile phone technology helps patients manage diabetes

Conference reports from: Athens, Madrid and New Orleans

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Bringing clinical evidence to practice in primary and secondary care

Contents 4

COVER STORY

Guest Editorial by Professor Jeyakumar Henry Glycaemic Index: Concept, recent developments and its role in diabetes

Volume 5 Issue 4 | August/September 2011 | ISSN 1753-464X

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ASTRO publishes white paper on IMRT safety

Teens with cancer facing unique challenges

Dentists could do frontline identification of undiagnosed diabetes

Dentists could identify undiagnosed diabetes Compounds found in tree can fight MRSA Mobile phone technology helps patients manage diabetes

Diabetes reports

Long-term use of antibiotics to treat acne

Atopic dermatitis - precursor to food allergies

International Congress on Neuropathic Pain

Athletes need early diagnosis and treatment of skin infections

Oncology reports

Dermatology reports

Conference reports from: Athens, Madrid and New Orleans

16 Athletes need early diagnosis and treatment of skin infections

Reports from the AAD, New Orleans

Reports from the ICNP, Athens

Clinical guideline for diagnosis and treatment of COPD released by US medical associations Respiratory report

ACC and the AHA issue consensus document for BP control in elderly Reports from the ACC, New Orleans

EMA Highlights

The BIG FOUR

World Health Matters

FDA Highlights

View from The Waiting Room

Emerging uses of EMA approved drugs

Reporting from some of the latest journal articles

Medical news from around the world

Emerging uses of FDA-approved drugs

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Guest editorial by Professor Jeyakumar Henry, Professor of Human Nutrition and Director of Functional Food Centre at Oxford Brookes University and Director of Clinical Nutrition at Singapore Institute of Clinical Science.

Glycaemic Index: Concept, recent developments and its role in diabetes

IET PLAYS AN important role in our lives. It plays an even more significant role in diabetes. Food Chemists have typically categorised dietary carbohydrates into simple sugars and complex carbohydrates on the basis of their degree of polymerisation. This form of classification of carbohydrates is a well established concept in Food Science. However, the effect of

The blood glucose response varies substantially among different carbohydrate containing foods and cannot be predicted by their gross chemical composition alone.

carbohydrate on health may be better categorised according to their physiological effects, notably their ability to raise blood glucose. The blood glucose response varies substantially among different carbohydrate containing foods and cannot be predicted by their gross chemical composition alone. This gave rise to the concept of the Glycaemic Index (GI). The concept of glycaemic index was first proposed by Jenkins et al 1 three decades ago. In fact it was devised as a tool to facilitate carbohydrate exchange in diabetics. GI is a

Contributors: Steve Devrell, Gary Finnegan, Professor Jeyakumar Henry, Peter Mas-Mollinedo, Samuel Peters, Bruce Sylvester

measure of the blood glucose raising ability of carbohydrate-rich foods. GI is expressed as a percentage of the incremental area under the glucose response curve (AUC) elicited in an individual after the consumption of food containing 50g available carbohydrate in comparison with the AUC elicited by 50g glucose in the same individual. The principle is that the slower the rate of carbohydrate absorption, the lower the rise of blood glucose level and the lower the GI value. A GI value of ≥70 is considered high, a GI value 56-59 inclusive is medium and a GI value ≤55 is low, where glucose=100.2 This important and innovative concept of classifying carbohydratecontaining foods has helped in the development of low GI diets that have preventive and therapeutic potential in diabetes, and weight maintenance.

Modulating Blood Glucose It is well recognised that postprandial glucose excursions are key contributors to the aetiology and complications of diabetes. Two large epidemiological studies have shown that a low GI diet reduces the risk of developing Type 2 diabetes. The risk was 37% higher in the highest quintiles of GI.3,4 A meta-analysis has shown that low GI diets can also improve blood glucose control in Type 1 and Type 2 diabetes to the same extent as some drug therapy used to control postprandial blood glucose levels.5 Low GI diets were also found to decrease fructosamine and HbA1c levels in people with Type 2 diabetes.6 All this is good news; an increase in 1mmol/L in postprandial blood glucose resulted in a 7% increase in total

Editorial / Advisory Board: Omar Ali Bsc MRPhamS, Y Callan MD MRCGP M Gray MRPharmS, M Gupta MD MRCP Tim Lewis MD FRCP, K O’Neill Bsc MRCGP Mr Ian Pearce, C Weston MD MRCP

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mortality over a 5-10 year period.7 GI of a food may be influenced by several factors including the particle size, food structure, ripeness, ratio of amylose and amylopectin, starch structure, level of food processing, cooking technique and the presence of other macronutrients such as fat and protein. The GI of white bread, potato and pasta can all be reduced by the addition of cheese, tuna or baked beans. The addition of fat to a carbohydrate food can significantly reduce the glycaemic response by increasing the viscosity of the intestinal contents and delaying the rate of gastric emptying. The addition of protein to a carbohydrate food may either inhibit glycolytic enzymes or increase the amount of insulin secreted, causing the blood glucose levels to be affected. The GI of foods can also be lowered using carbohydrate-based ingredients such as modified celluloses, soluble fibres from barley and oats, legumes rich in galactomannans. Using such ingredients, several bakery and other products have now emerged in the global market.9,10 Research has shown that the substitution of high-GI bread by low-GI bread at breakfast, lunch and dinner can favourably alter 24h glucose profile in healthy subjects.8

GI and Carbohydrate Quality The international table of glycaemic index and glycaemic load values published recently lists 2,487 different items across a wide range of food products.11 As a rule of thumb, highly processed and refined foods have a high GI. Unpolished or minimally processed cereals have a low GI. In addition, all soy and dairy-based products, lentils and legumes, wholegrain and

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© ICR-UK Limited. The information contained in Evidentia is intended to be used with professional medical knowledge and in conjunction with other sources of clinical evidence and product literature. ICR-UK & sister company IMI, publish a number of medical jour nals and electronic jour nals. For more information visit www.icr-uk.com ICR-UK are affiliate members of the ABPI ISSN: 1753-464X Designed by JAM Design 01483 426017 P r i n t e d b y S t e p h e n s & G e o r g e 0 1 6 8 5 3 8 8 8 8 8 D i s t r i b u t e d b y P r e c i s i o n M a r k e t i n g G r o u p 0 1 2 8 4 7 1 8 9 0 0

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multiseeds, certain pastas are predominantly low GI foods. Satiety effects of low-GI foods may be due to reduction in gastric emptying or by an increase in fat oxidation at the expense of carbohydrate oxidation. High fibre content of some low GI foods prolong distension of the gastrointestinal tract, causing secretion of the gut peptides cholecystokinin, ghrelin, glucagon, glucagonlike-peptide-1 and glucose-dependent insulinotropic polypeptide resulting in satiety. Infants born to women following a low GI diet were found to be of normal size with less body fat than babies born to women following a high GI diet.12 Despite GI’s health benefits in diabetes management and its recent popularity, scientists still argue about its usefulness. Wolever et al 13 recently reported that GI is a significant determinant of glycaemic responses elicited by composite breakfast meals. In their study, carbohydrate content and GI were the only determinants of glycaemic response, reiterating that GI is a significant determinant of mixed meals when properly applied in realistic settings. Many international diabetes organisations such as Canadian Diabetes Association, Diabetes Australia, Diabetes UK and the European Association for the Study of Diabetes favour the application of GI in diabetes management. Low GI foods are often packed with high levels of fibre, antioxidants and phytochemicals that are beneficial to health. For several decades the diet-chronic disease paradigm has centred around reducing the intake of saturated fat, cholesterol, and increasing the consumption of

complex carbohydrates. The type of carbohydrate we consume may be as or more important than the type of fat we consume: It is here that the concept of Glycaemic Index may

As a rule of thumb, highly processed and refined foods have a high GI. Unpolished or minimally processed cereals have a low GI. In addition, all soy and dairy-based products, lentils and legumes, wholegrain and multiseeds, certain pastas are predominantly low GI foods.

have a significant role to play. The increased intake of refined carbohydrates (i.e.) high GI carbohydrates in most Western diets may have aggravated the incidence of obesity and diabetes. A rethink of the type of carbohydrates we eat may be long overdue.

References: 1. Jenkins DJA, Wolever TMS, Taylor RH, Barker H, Fielden H, Baldwin JM, Bowling AC, Newman HC, Jenkins AL and Goff DV. Glycemic index of foods: a physiological basis for carbohydrate exchange. American Journal of Clinical Nutrition 1981; 34: 362 – 366

2. Brand Miller J, Foster Powell K and Colaguiri S. The New Glucose Revolution. New York, Marlowe and Company; 2003 3. Salmeron J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett WC. Dietary fibre, glycemic load, and risk of noninsulin- dependent diabetes mellitus in women. JAMA. 1997; 277: 472-477 4. Salmeron J, Ascherio A, Rimm E, et al. Dietary fibre, glycaemic load and risk of NIDDM in men. Diabetes Care. 1997; 20: 545-550 5. Brand-Miller J, Hayne S, Petocz P, et al. Low-glycemic index diets in the management of diabetes: a metaanalysis of randomized controlled trials. Diabetes Care 2003; 26: 2261-2267 6. Opperman AM, Venter CS, Oosthuizen W et al. Meta-analysis of the health effects of using the glycaemic index in meal-planning. Br J Nutr 2004; 92: 367-381 7. The DECODE Study Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 1999; 354: 617-621 8. Henry CJK, Lightowler HJ, Tydeman EA and Skeath R. Use of low-glycemic index bread to reduce 24-h blood glucose: implications for dietary advice to nondiabetic and diabetic subjects. International Journal of Food Sciences and Nutrition 2006; 57: 273 – 278 9. Henry CJK and Lightowler HJ. Glycemic response of mashed potato containing high-viscosity hydroxypropylmethyl cellulose. Nutrition Research 2009a; 29: 551 – 557 10. Thondre PS and Henry CJK. High molecular weight barley β-glucan in chapattis (unleavened flat breads) lowers glycemic index. Nutrition Research 2009; 29: 480-486 11. Atkinson FS, Foster-Powell K and Brand-Miller JC. International Table of glycemic index and glycemic load values: 2008. Diabetes Care 2008; 31: 22812283 12. Brand JC, Colaguiri S, Crossman S, Allen A, Roberts DC and Truswell AS. Low glycemic index foods improve long-term glycemic control in NIDDM. Diabetes Care 1991; 14: 95 – 101 13. Wolever TMS, Yang M, Zeng XY, Atkinson F and Brand-Miller JC (2006). Food glycemic index, as given in glycemic index tables, is a significant determinant of glycemic responses elicited by composite breakfast meals. American Journal of Clinical Nutrition 2006; 83: 1306 – 1312.

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Oncology reports

ASTRO publishes white paper on IMRT safety

S PART OF THE Target Safely initiative, the American Society for Radiation Oncology (ASTRO) has developed a white paper, the first of a series of such papers, on the safe use of integrating intensity modulated radiation therapy (IMRT) into the radiation oncology clinic. The executive summary of this white paper is published in the July print issue of Practical Radiation Oncology, ASTRO's clinical practice journal. The full text of the document is available in advance of print online at www.practicalradonc.org.

Radiation therapy has been used safely and effectively for more than 100 years to treat cancer. In the past few decades, researchers have created new techniques for delivering radiation that further target the tumour while sparing nearby healthy tissue, thus improving the chances of a cure while minimising side effects. One such technique is called intensity modulated radiation therapy or IMRT. IMRT is a tremendous advance in the safe and effective delivery of radiation. However, it also requires much more time and resources from cancer clinics, radiation oncologists, physicists, radiation therapists, dosimetrists, nurses and their support staff to be done correctly.

Errors in radiation therapy are extremely rare, but ASTRO's leadership knows that even one error, however minor, is too many. That's why ASTRO began the Target Safely initiative to help the radiation oncology community further prevent treatment delivery mistakes. The main concerns raised in this white paper are: 1. IMRT is a time and resource intensive procedure. Practitioners must work together as a team to address environmental and technical concerns to improve patient safety. 2. Timely treatment is important. However, pressure and real-time changes to treatment plans can lead to errors. This report encourages the use of standard operating procedures and "forced time outs" to assure adequate time to perform reviews or quality assurance at key points in the process. 3. Team members need to acknowledge that delays in initiation of treatment may be necessary to allow adequate time for quality assurance checks and to investigate any problems discovered. The report also provides practical guidance that radiation oncology treatment teams can use in their clinics to improve safety. This

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guidance includes identifying the key components of an IMRT system, an example of the roles and responsibilities within the IMRT planning and delivery process, a list of examples of possible problems that may occur within the process along with possible remedial actions, and a list of recommendations to guard against catastrophic failures for IMRT. "Intensity modulated radiation therapy has been a tremendous advance in the way we treat patients by improving the planning and delivery of radiation therapy. IMRT and other advances in radiation therapy can be used to deliver high doses to tumours while decreasing the dose to healthy tissues," Jean M. Moran, PhD, lead author of the study, Associate Professor and the Associate Division Director for Clinical Physics at the University of Michigan Medical Center in Ann Arbor, Mich., said. "IMRT is, however, incredibly time and resource intensive. It involves the use of sophisticated software and delivery systems and many hand-offs between team members throughout the simulation, planning, and

“Intensity modulated radiation therapy has been a tremendous advance in the way we treat patients by improving the planning and delivery of radiation therapy.”

delivery process. It is our hope that practitioners will use the tools and techniques presented in this document to reassess and strengthen their own IMRT programmes." For a copy of the white paper, visit www.astro.org/research or www.practicalradonc.org. For further information contact: Beth Bukata bethb@astro.org

Medical oncology recognised at EU level to allow free movement of doctors

HE EUROPEAN SOCIETY for Medical Oncology (ESMO), the leading professional organisation for medical oncology in Europe, announced that medical oncology has been included among the medical specialties covered by Directive 2005/36/EC on the recognition of professional qualifications, as announced yesterday by the Commission. The decision was taken after several years of intense discussion between ESMO, key national societies and EU Member States. "This is an important step towards better cancer care in Europe," said ESMO President Professor David Kerr. The inclusion of medical oncology in the Directive will in fact improve the mobility of medical oncologists in Europe, with their professional qualifications being 'automatically recognised' amongst participating EU Member States in accordance with EC Directive. "In light of the increasingly important role played by medical oncologists in the comprehensive management of cancer

patients, free movement of medical oncologists will be beneficial to address the growing cancer burden, allowing to cope with potential labour shortages more promptly," Professor Kerr added. The decision made by Member States will also act as an extra incentive to young medical oncologists looking for stimulating and exciting opportunities abroad, both in the research and the clinical sectors, allowing them to become more competitive and operate in a more stimulating context, without being hindered by bureaucratic barriers. "Demographic trends will provoke a shortage of medical oncologists in cancer care," noted Dr. Paolo Casali, ESMO Public Affairs Chair. "It was ESMO's duty to work for a more uniform and harmonised European setting, where cancer patients can benefit from the professionalism of medical oncologists irrespective of where they live," Casali concluded.

Cancer care and demographic trends in Europe With an estimated 3.2 million new cases (53% occurring in men, 47% in women) and 1.7 million deaths (56% in men, 44% in women) each year, cancer remains an important public health problem in Europe. The total number of new cases of cancer in Europe appear to have increased by 300,000 between 2004 and 2006. The ageing of the European population will cause these numbers to continue to increase even if age-specific rates remain constant. Demographic trends will provoke a shortage of medical oncologists in cancer care. Already some countries feel the need to employ foreign-trained medical oncologists to ensure patients have access to specialist care. Also in larger member states such as Spain, the supply of medical oncologists is an issue. The Spanish Society of Medical Oncology (SEOM) reported an estimated shortage of 1,100 medical oncologists in 2009.

IASLC launches Staging Atlas in Thoracic Oncology application

HE INTERNATIONAL ASSOCIATION for the Study of Lung Cancer (IASLC), the only global organisation dedicated to the study of lung cancer, today announced the release of its ‘Staging Atlas in Thoracic Oncology’ as a downloadable application for iPad, iPhone, Android or BlackBerry. The app, which puts the most up-to-date TNM (tumour, node, metastasis) staging information in the hands of doctors and patients living with cancer, is available in English, French, German, Japanese, Italian, Spanish and Chinese.

The Staging Atlas was developed in collaboration with the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). It's the first-ever site-specific guide on the TNM classification of thoracic malignancies. With its IASLCoriginal illustrations, beautifully rendered specifically for iPad and smartphone media, it serves as a complement to and enhancement of the AJCC and UICC staging publications. This interactive staging tool for on-the-spot

verification of the most up-todate TNM classification variables is especially valuable to oncologists, surgeons, radiologists and scientists working in the field of thoracic oncology. It can be ordered through IASLC's website, http://iaslc.org/, or at the following sites: Appshopper (for iPad and iPhone): CONTINUED ON PAGE 8 >

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Oncology reports

Teens and young adults with cancer face unique challenges and require targeted care

DOLESCENTS AND YOUNG adults (AYA) are neither children nor adults and those affected by cancer require targeted care that crosses the boundaries between paediatric and adult oncology, according to several pioneers in this still-developing field of adolescent and young adult oncology. An illuminating roundtable discussion by these experts has been published in the first issue of Journal of Adolescent and Young Adult Oncology, a multidisciplinary peerreviewed publication (www.liebertpub.com). "AYA cancer presents the medical community with several unique problems. First, it requires true collaboration between paediatric and medical oncologists as the age range crosses both disciplines. Next, our AYA cancer patients not only have cancer but are also often dealing with ongoing developmental and psychosocial issues at the same time; as such, we must be aware of how a cancer diagnosis interferes with their normal development. The roundtable discussion helps put AYA cancer in perspective for those who have not yet considered the 15-39 year old cancer patient as a distinct and relevant patient group," according to editor-in-chief Leonard S. Sender, MD, of the University of California, Irvine and

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http://appshopper.com/medical/iaslc-stagingresource-in-thoracic-oncology Android Market: https://market.android.com/search?q=iaslc +staging&c=apps&price=0&so=1 BlackBerry App World: https://appworld.blackberry.com/webstore/ content/41679?lang=en For more information about the IASLC Staging Atlas in Thoracic Oncology applications, contact info@editorialrxpress.com. For further information contact: Renée McGaw renee.mcgaw@ucdenver.edu

CHOC Children's Hospital. The roundtable discussion, "Trailblazers in Adolescent and Young Adult Oncology," was moderated by Archie Bleyer, MD, Medical Director of Clinical Research for the St. Charles Health System in Bend, Oregon. Participants were leading physicians of paediatric, adolescent, and young adult oncology who

Several factors contributed to the growing recognition that adolescents and young adults have not enjoyed the same improvements in overall survival compared with their younger and older peers. have helped mould and advance this area of specialization trace the history and driving forces behind programmes and disease management strategies now in place that target this patient population. Representing the experiences and revolutionary changes that have taken place in the United States, England and Canada, Dr. Bleyer was joined by Karen Albritton, MD, Director of the Adolescent and Young Adult Oncology Programme at Cook Children's Medical Center and University of North Texas Health Science Center in Fort Worth; Ronald Barr, MB ChB, MD, Professor of Paediatrics,

Pathology and Medicine at McMaster University in Canada; Ian Lewis, MB ChB, Professor of Cancer Research in Children and Young People at Leeds Teaching Hospital in the United Kingdom; and Editor-in-Chief Leonard Sender, MD, Medical Director of the Cancer Institute at CHOC Children's Hospital and Director of the Young Adult Cancer Program at the University of California, Irvine's Chao Family Comprehensive Cancer Center in Orange, CA. Several factors contributed to the growing recognition that adolescents and young adults defined by the National Cancer Institute as patients aged 15 to 39 at diagnosis - are a distinct group of cancer patients that have not enjoyed the same improvements in overall survival compared with their younger and older peers. The reasons for the differences have not been fully elucidated but many suspect multiple factors working independently or together, including biological differences, treatment protocol or medical care facility variances, lack of relevant clinical trials, and access to care due to un- or under-insured status. In addition to those newly diagnosed as an AYA, there is a growing community of AYAs who are survivors of paediatric cancer. Research has demonstrated that cancer is a chronic disease and that survivorship is often fraught with unintended consequences of cancer treatment, including infertility, heart and lung damage, and metabolic problems. Survivorship issues, both of the paediatric cancer survivor and the AYA cancer survivor, will be addressed in the new journal from Liebert.

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Diabetes reports by Bruce Sylvester

Dentists could do frontline identification of undiagnosed diabetes

OUTINE DENTAL CARE is an opportunity to spot persons with undiagnosed diabetes or prediabetes, American researchers reported in the recent issue of the Journal of Dental Research. "Periodontal disease is an early complication of diabetes, and about 70% of U.S. adults see a dentist at least once a year," said lead investigator Dr. Ira Lamster, dean of the College of Dental Medicine at Columbia University College of Dental Medicine in New York. "Prior research focused on identification strategies relevant to medical settings. Oral healthcare settings have not been evaluated before, nor have the contributions of oral findings ever been tested prospectively." The investigators recruited approximately 600 subjects at a dental clinic in New York City. They

were 40-years-old or older if non-Hispanic and white and 30-years-old or older if Hispanic or non-white. They had never been diagnosed with diabetes or pre-diabetes. Approximately 530 patients with at least one additional self-reported diabetes risk factor (family history of diabetes, high cholesterol, hypertension, or overweight/obesity) received a periodontal examination and a fingerstick, point-of-care haemoglobin A1c test. To refine the analysis by comparison to the initial examination, the subjects returned for a fasting plasma glucose test to definitively identify pre-diabetes and diabetes. The investigators reported that, in this at-risk dental population, a simple algorithm using number of missing teeth and percentage of deep periodontal pockets was effective in identifying

patients with unrecognised pre-diabetes or diabetes. The addition of the point-of-care A1c test improved the accuracy of the algorithm. "Early recognition of diabetes has been the focus of efforts from medical and public health colleagues for years, as early treatment of affected individuals can limit the development of many serious complications," says Dr. Evanthia Lalla, an associate professor at the College of Dental Medicine, and the lead author on the paper. "Relatively simple lifestyle changes in prediabetic individuals can prevent progression to frank diabetes, so identifying this group of individuals is also important," she adds. "Our findings provide a simple approach that can be easily used in all dental-care settings." Source : Columbia University Medical Center

How fatty diets cause diabetes High levels of fat shut down a key enzyme that promotes glucose sensing in pancreatic beta cells - revealing a pathway implicated in the Type 2 diabetes epidemic.

EWLY DIAGNOSED Type 2 diabetics tend to have one thing in common: obesity. Exactly how diet and obesity trigger diabetes has long been the subject of intense scientific research. A new study led by Jamey D. Marth, Ph.D., director of the Center for Nanomedicine, a collaboration between the University of California, Santa Barbara and Sanford-Burnham Medical Research Institute (Sanford-Burnham), has revealed a pathway that links high-fat diets to a sequence of molecular events responsible for the onset and severity of diabetes. These findings were published online recently in Nature Medicine. In studies spanning mice and humans, Dr. Marth's team discovered a pathway to disease that is activated in pancreatic beta cells, and then leads to metabolic defects in other organs

and tissues, including the liver, muscle and adipose (fat). Together, this adds up to diabetes. "We were initially surprised to learn how much the pancreatic beta cell contributes to the onset and severity of diabetes," said Dr. Marth."The observation that beta cell malfunction significantly contributes to multiple disease signs, including insulin resistance, was unexpected. We noted, however, that studies from other laboratories published over the past few decades had

alluded to this possibility." In healthy people, pancreatic beta cells monitor the bloodstream for glucose using glucose transporters anchored in their cellular CONTINUED ON PAGE 10 >

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Diabetes reports by Bruce Sylvester

Positive news for linagliptin

YPE 2 DIABETES patients with impaired renal function saw significant drops in HbA1c after treatment with linagliptin when compared with placebo, researchers said . In a 12-week trial that enrolled patients with insufficiently controlled hyperglycaemia and severe renal dysfunction, glycosylated haemoglobin (HbA1c) dropped by 0.76 percentage points in those who received linagliptin compared with a 0.18 percentage point reduction among placebo patients (P<0.0001), said Lance Sloan, MD, of the Texas Institute for Kidney and Endocrine Disorders in Lufkin. Sloan and colleagues randomised 133 patients to either once-daily linagliptin (5mg) or placebo in addition to their prescribed antidiabetic background therapy. The participants in the trial were required to have an HbA1c of 7% to 10% and also have severe renal disease with an estimated GFR of less than 30mL/min/1.73m2. While declining renal function is a frequent complication of Type 2 diabetes, the management of Type 2 patients with renal impairment may be difficult, Sloan said. Several

oral antidiabetic drugs, such as metformin, should not be used because of safety and tolerability issues. Others drugs are associated with side effects such as fluid retention or

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transporters in the cell membrane depends on this modification, but when FOXA2 and HNF1A aren't working properly, GnT-4a's function is greatly diminished. So when the researchers fed otherwise normal mice a high-fat diet, they found that the animals' beta cells could not sense and respond to blood glucose. Preservation of GnT-4a function was able to block the onset of diabetes, even in obese animals. Diminished glucose sensing by beta cells was shown to be an important determinant of disease onset and severity. "Now that we know more fully how states of over-nutrition can lead to Type 2 diabetes, we can see more clearly how to intervene," Dr. Marth said. He and his colleagues are

membranes. When blood glucose is high, such as after a meal, beta cells take in this additional glucose and respond by secreting insulin in a timed and measured response. In turn, insulin stimulates other cells in the body to take up glucose, a nutrient they need to produce energy. In this newly discovered pathway, high levels of fat were found to interfere with two key transcription factors - proteins that switch genes on and off. These transcription factors, FOXA2 and HNF1A, are normally required for the production of an enzyme called GnT-4a glycosyltransferase that modifies proteins with a particular glycan (polysaccharide or sugar) structure. Proper retention of glucose

"An important advantage of linagliptin is that we don't have to adjust the dose when treating patients with severe kidney dysfunction. It may be a better drug for these patients." Dr. Lance Sloan

hypoglycaemia, which limits treatment success, he said. "An important advantage of linagliptin is that we don't have to adjust the dose when treating patients with severe kidney dysfunction. It may be a better drug for these patients," Sloan said. The researchers noted that in the subgroup

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of patients with poorly controlled diabetes those with an HbA1c of 9% or greater treatment with linagliptin was associated with a 1.46 percentage point decline in HbA1c from baseline compared with a 0.28 percentage point decline from baseline in placebo patients. Adverse events were reported in 85.3% of linagliptin patients and 70.8% of placebo patients. Severe adverse events were observed in 13.2% of linagliptin patients and in 4.6% of placebo patients. Severe hypoglycaemia occurred in 3% of the linagliptin patients but was not observed among the placebo patients. Sloan said most cases of hypoglycaemia with linagliptin were mainly asymptomatic or mild in intensity and may be explained by the unchanged glucose-lowering treatment background, which was insulin in most cases. He said that the protocol of the trial did not allow changes in the background medication. Renal parameters and blood potassium levels remained unchanged with linagliptin. One cardiac death occurred among the linagliptintreated patients and three cardiac deaths occurred in placebo-treated patients, the CONTINUED ON PAGE 12 >

now considering various methods to augment beta cell GnT-4a enzyme activity in humans, as a means to prevent and possibly cure Type 2 diabetes. "The identification of the molecular players in this pathway to diabetes suggests new therapeutic targets and approaches towards developing an effective preventative or perhaps curative treatment," Dr. Marth continued. "This may be accomplished by beta cell gene therapy or by drugs that interfere with this pathway in order to maintain normal beta cell function." For further information contact: Heather Buschman, Ph.D. hbuschman@sanfordburnham.org

Together we can tackle DIABETES Boehringer Ingelheim and Eli Lilly have formed a 20-year strategic alliance to bring new diabetes treatments to patients around the world. This major diabetes care agreement centres on four pipeline compounds representing several product classes currently in development. Diabetes is now a global pandemic â&#x20AC;&#x201C; and by 2030 it is estimated that it will affect 438 million people worldwide.1 Over the next two decades, together we are really going to tackle this major threat to world health.

1. www.diabetesatlas.org/content/foreword. DIB0209 Date of preparation: April 2011

Diabetes reports by Bruce Sylvester

Positive news for linagliptin < CONTINUED FROM PAGE 10

researchers reported. Sloan said that the study is the first to examine the safety and efficacy of a dipeptidyl peptidase-4 inhibitor exclusively in patients with severe renal impairment."This is further clinical evidence that the pharmacology of this drug appears to be sustained in patients with severe renal impairment," said David Kendall, MD, chief scientific and medical officer for the ADA. "This

“This will be an important step forward in the management of Type 2 diabetes in Europe.” Professor Anthony Barnett

suggests that linagliptin has the ability to be safely dosed in chronic kidney disease patients the more severe the renal disease, the less likely one is to use metformin because of safety concerns. Linagliptin gives us an option in these patients," he said. In June 2011, Boehringer Ingelheim and Eli Lilly and Company, the makers of linagliptin, received a positive response from the European Medicines Agency’s (EMA) Medicinal Committee recommending that linagliptin in the 5mg dose, film-coated tablets, be approved for use in Europe. “The Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of linagliptin as a monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to intolerance, or contraindicated due to renal impairment.” They are also recommending that linagliptin might be used in combination with metformin and metformin plus sulfonylurea. Their research showed that when linagliptin was used in conjunction with metformin, it reduced the A1c levels by 0.6 to 0.7% when compared to the use of a placebo.

The positive opinion for the use in Europe of linagliptin was based on a clinical trial programme that involved approximately 4,000 adults with Type 2 diabetes. Professor Anthony Barnett, Clinical Director, Department of Diabetes and Endocrinology, University of Birmingham and Heart of England NHS, UK, was quoted as saying, “This will be an important step forward in the management of Type 2 diabetes in Europe.” Furthermore, he stated, “Of note, linagliptin is primarily excreted via the bile and gut, meaning no dose adjustment is recommended in patients with kidney or liver impairment. Therefore, this will be the first DPP-4 inhibitor available at one dose for all adult patients with Type 2 diabetes.” Type 2 diabetes has increasingly been

diagnosed around the world. Linagliptin will be a new treatment available in the UK for those suffering from Type 2 diabetes and are having difficulties controlling their blood sugar levels.

Disclosure: Funding for the study was provided by Boehringer Ingelheim. Sloan disclosed financial relationships with Boehringer Ingelheim, Abbott Diabetes Care, Amgen, GlaxoSmithKline, Merck and Novatis. Co-authors include employees of Boehringer Ingelheim. Kendall had no relevant disclosures. Reference: Sloan L et al, "Safety and efficacy of linagliptin in Type 2 diabetes patients with severe renal impairment," Diabetes 2011; 60 Supplement (1) A114

is a FREE request only e-journal for healthcare professionals delivered to you by email To receive this electronic journal please email: subscriptions@icr-uk.com and mark your email ʻDiabetes.MEDʼ

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Mobile phone technology helps patients manage diabetes Trial is one of the first to include a control group and follow patients for a year.

N INTERACTIVE COMPUTER software programme appears to be effective in helping patients manage their Type 2 diabetes using their mobile phones, according to a new study by University of Maryland School of Medicine researchers. The study has been published in a recent issue of the journal Diabetes Care. The study, one of the first to scientifically examine mobile health technology, found that a key measure of blood sugar control – the amount of haemoglobin A1c in a person's blood – was lowered by an average of 1.9% over a period of one year in patients using the mobile health software. The findings support the further exploration of mobile health approaches to manage many chronic conditions, including diabetes.

Three patient groups received mobile phones loaded with the diabetes management software and the fourth group served as a control group.

patients and their physicians manage many health conditions. "Mobile health has the potential to help patients better self-manage any chronic disease, not just diabetes," Dr. Quinn explains. "This is one of the first large, reported, randomised clinical studies examining the mobile health industry, which is rapidly growing. The U.S. Food & Drug Administration just last month released draft guidance on how it intends to regulate the field. Our results can help define the science behind this new strategy for disease management." An A1c test provides a snapshot of a patient's average daily blood glucose levels over the previous two to three months. The American Diabetes Association recommends that a person's A1c be less than 7%. Most Americans with Type 2 diabetes have an average level of more than 9%, which greatly increases their risk for complications. "We tell patients that they can meet these goals if they eat a healthy diet, exercise daily and take their medication as directed, but we don't really give them the tools to do that," says Dr. Quinn. The year-long study enrolled 163 patients

with the help of 39 primary care doctors in Baltimore County, Baltimore City, Montgomery County and Anne Arundel County. Patients were divided into four groups based on the research assignment of their physician. Three patient groups received mobile phones loaded with the diabetes management software and the fourth group served as a control group. All patients in the study received a free blood glucose meter and testing supplies. The software examined in the research provided real-time feedback on patients' blood sugar levels, displayed medication regimens and served as a "virtual coach". A patient's blood sugar test results were sent wirelessly from a blood glucose monitor to the mobile phone. If the level was too low or too high, the software on the phone prompted the person to take steps to correct it. The system also analysed blood sugar levels and other patient information and sent computer-generated logbooks and suggested treatment plans to the patients' primary care doctor. For further information contact: Karen Warmkessel kwarmkessel@umm.edu

"These results are very encouraging," says Charlene C. Quinn, Ph.D., R.N., an assistant professor of epidemiology and public health at the University of Maryland School of Medicine and the principal investigator. "The 1.9% decrease in A1c that we saw in this research is significant. Previous randomised clinical trials have suggested that just a 1% decrease in A1c will prevent complications of diabetes, including heart disease, stroke, blindness and kidney failure." The study indicates that using mobile phones, the Internet and other mobile communications technology to keep patients healthy may have broad applications to help E V I D E N T I A • V O L U M E 5 • I S S U E 4 • AU G U S T / S E P T E M B E R 2 0 1 1

Dermatology reports by Samuel Peters

Long-term use of antibiotics to treat acne

HE PROLONGED USE of tetracycline antibiotics commonly used to treat acne was associated with a reduced prevalence of Staphylococcus aureus bacteria and was not associated with increased resistance to the tetracycline antibiotics, according to a report posted online that will appear in the August print issue of Archives of Dermatology. S. aureus is found in both hospital and community settings. "While S. aureus colonises the skin, it can also be responsible for localised cutaneous infections and life-threatening systemic infections," the authors write as background information in the article. "At one time, it was sensitive to many antibiotics and antimicrobial agents. However, because of its ability to adapt to these therapies and become resistant, clinical scenarios now exist in which few therapeutic options remain to treat this organism. Therefore, methicillin-resistant

S. aureus (MRSA) has become commonplace." Matthew Fanelli, M.D., and colleagues at the University of Pennsylvania School of Medicine, Philadelphia, conducted a survey study of patients treated for acne to determine the frequency of S. aureus colonisation and to compare the susceptibility patterns between patients who are using antibiotics and those who are not using antibiotics. A total of 36 of the 83 patients in the study (43%) were colonised with S. aureus. Two of the 36 patients (6%) had MRSA; 20 (56%) had S. aureus solely in their throats; nine (2%) had S. aureus solely in their noses; and seven (19%) had S. aureus in both their noses and throats. "Long-term use of antibiotics decreased the prevalence of S. aureus colonisation by nearly 70%," the authors report. "A decreased rate of colonisation was noted with the use of both oral and topical antibiotics." "Fewer than 10% of the isolates of S. aureus

were resistant to tetracyclines, the most commonly used antibiotic family to treat acne," they write. "Resistance to erythromycin and clindamycin was mostly prevalent among our isolates and was noted in the patients who did and did not use antibiotics." The study results contradict current dogma about long-term use of antibiotics. "Specifically, in our study, the prolonged use of antibiotics from the tetracycline class that are commonly used to treat acne lowered the prevalence of colonisation by S. aureus and did not increase resistance to the tetracycline antibiotics," the authors conclude. "Future research should be conducted with respect to other organisms and antibiotics." Arch Dermatol. Published online April 11, 2011. doi:10.1001/archdermatol.2011.67. For further information contact: Kim Menard kim.menard@uphs.upenn.edu

Chemical compounds in trees can fight MRSA

"TRASH TREE," one with little economic value and often removed by farmers due to its ability to destroy farmland, could be the key to fighting a deadly bacterium. Now, a University of Missouri researcher has found an antibiotic in the Eastern Red Cedar tree that is effective against methicillinresistant Staphylococcus aureus (MRSA). "I wanted to find a use for a tree species that is considered a nuisance," said Chung-Ho Lin, research assistant professor in the MU Center for Agroforestry at the College of Agriculture, Food and Natural Resources. "This discovery could help people fight the bacteria as well as give farmers another cash crop." MRSA is an evolving bacterium that is resistant to most medications. For most people, the infection is isolated to the skin. However, it can spread to vital organs causing toxic shock syndrome and pneumonia, especially in people with weakened immune systems. The incidence of disease caused by MRSA bacteria is increasing worldwide. Thirty years ago, MRSA

accounted for 2% of all staph infections. By 2003, that number had climbed to 64%. In 2005, more than 94,000 people developed lifethreatening MRSA infections in the United States, according to a Centers for Disease Control report. Nearly 19,000 people died during hospital stays related to these infections. While the Eastern Red Cedar has few commercial uses, it is present in the U.S. in large numbers and its range extends from Kansas to the eastern United States. An estimated 500 million trees grow in Missouri. Lin began his investigation by building on existing research showing the anti-bacterial potential of chemical compounds derived from the tree. Lin, George Stewart, professor and department chair of Pathobiology in the College of Veterinary Medicine, and Brian Thompson, postdoctoral fellow in the Bond Life Sciences Center, identified, isolated and tested 17 bioactive compounds and have plans to analyse more compounds. Scientists found that a relatively small concentration of a chemical

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compound found in the Eastern Red Cedar- five micrograms per millilitre - was effective against MRSA. The team tested the compound's effectiveness against many versions of MRSA in a test tube with promising initial results. "We found this chemical from the cedar needles, an abundant and renewable resource that can be collected annually," co-researcher Brian Thompson said. "Because the compound is in the needles, we don't have to cut down the trees." In addition to its potential use in fighting MRSA, researchers found that some chemical compounds in the tree are able to fight and kill skin cancer cells present in mice. It may also be effective as a topical acne treatment. Stewart said the compounds are years away from commercial use, as they must go through clinical trials. The team's research was presented recently at the International Conference on Gram-Positive Pathogens. For further information contact: Christian Basi BasiC@missouri.edu

This weekend

This summer

This time next year

She wants fast results. You want long-term results. Introducing an acne therapy that keeps you both happy Epiduo Gel Abbreviated Prescribing Information Presentation: 0.1% adapalene & 2.5% benzoyl peroxide Indications: Cutaneous treatment of acne vulgaris when comedones, papules and pustules are present. Dosage and Administration: A thin film should be applied to the entire acne affected areas once a day in the evening to clean & dry skin. If irritation occurs, apply non-comedogenic moisturizers, use the medication less frequently, suspend use temporarily, or discontinue use altogether. Duration of treatment should be determined on the basis of clinical condition; early signs of improvement usually appear after 1 to 4 weeks. The safety and effectiveness of Epiduo have not been studied in children below 12 years of age. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Precautions and Warnings: Should not be applied to damaged, broken or eczematous skin, or come into contact with eyes, mouth, nostrils or mucous membranes (wash immediately with warm water if product enters eyes). Contains propylene glycol (E1520) which may cause skin irritation. Avoid excessive exposure to sunlight or UV light. Avoid contact with any coloured material including hair and dyed fabrics as this may result in bleaching and discoloration. Epiduo should not be used during pregnancy. Interactions: No interaction studies have been conducted with Epiduo. There are no known interactions with other medicinal products which might be used cutaneously and concurrently with Epiduo. However, other retinoids, benzoyl peroxide or drugs with a similar mode of action should not be used concurrently. Caution should be exercised if cosmetics with desquamative, irritant or drying effects are used, as they may produce additive irritant effects with Epiduo. Absorption of adapalene & benzoyl peroxide through human skin is low therefore interaction with systemic medicinal products is unlikely.

Undesirable Effects: Epiduo may cause the following localized adverse reactions: Common (≥ 1/100 to <1/10): dry skin, irritative contact dermatitis, burning and skin irritation. Uncommon (≥ 1/1000 to ≤1/100): pruritus and sunburn. Unknown (cannot be estimated from the available data): allergic contact dermatitis, swelling face. If skin irritation appears after application of Epiduo, the intensity is generally mild or moderate, with local tolerability signs and symptoms (erythema, dryness, scaling, burning and pain of skin (stinging pain)) peaking during the first week and then subsiding spontaneously. Packaging Quantities and Cost: 45g tube £17.91 (NHS) MA Number: PL 10590/0057 Legal Category: POM Full Prescribing Information is Available From: Galderma (UK) Limited, Meridien House, 69-71 Clarendon Road, Watford, Herts, WD17 1DS. UK. Tel: +44 (0)1923 208950 Fax: +44 (0)1923 208998. Date of Revision: November 2010.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Galderma (UK) Ltd. Date of preparation: January 2011 EPI/508/0111 Copyright © 2011 Galderma (UK) Ltd.

American Academy of Dermatology Reports from the AAD, New Orleans by Bruce Sylvester

The AAD held its 69th Annual Meeting in New Orleans, earlier this year, with more than 17,000 attendees. The meeting featured presentations of the latest research in the diagnosis and medical, surgical and cosmetic treatment of skin, hair and nail conditions. Here are some highlights from the meeting:

Atopic dermatitis - precursor to food allergies

TOPIC DERMATITIS, ONE of the most common forms of eczema, is a precursor to allergic diseases rather than a consequence, researchers reported at AAD. And new guidelines have been developed to bring this correlation into standard paediatric care. Jon Hanifin, MD, professor of dermatology at Oregon Health & Science University in Portland, discussed the link between atopic dermatitis and food allergies, as well as the new food allergy guidelines issued in December 2010 by the (US) National Institute of Allergy and Infectious Diseases (NIAID). “Considering that six to 10% of children have atopic dermatitis and that up to onethird of those individuals may have documented food allergy, the number of these children affected by food allergies may be significant,” said Dr. Hanifin. “In most

cases, patients experience atopic dermatitis before food allergies, so it is important for parents of infants and small children affected by this skin condition to be aware of the risk of food allergies.” In a recently reported, five-year, multi-centre study by Dr. Hanifin and colleagues, 15% of children age three to 18 months with even mild cases of atopic dermatitis showed definite food allergies. Dr. Hanifin noted that subjects with more severe cases of atopic dermatitis generally had a higher incidence of food allergies. Although this study and others confirm the strong correlation between atopic dermatitis and food allergies, proper testing for a food allergy – as recommended in the new guidelines – is critical in determining if an actual food allergy exists. The new guidelines recommend that, “…children less than five years old with

moderate to severe atopic dermatitis be considered for food allergy evaluation for milk, egg, peanut, wheat and soy, if at least one of the following conditions are met: The child has persistent atopic dermatitis in spite of optimised management and topical therapy. The child has a reliable history of an immediate reaction after ingestion of a specific food.” Dr. Hanifin noted that, in the past, positive blood tests and skin tests would be mistaken for a food allergy, because they would indicate the presence of IgE antibodies, which are higher in patients with atopic dermatitis. “However, those antibodies are not diagnostic, and the only way to diagnose food allergy is with a strong history of reactions or a challenge – where you feed patients the food indicated by tests and see if they have an immediate reaction to it.”

Athletes need early diagnosis of infected skin

HYSICAL CLOSENESS typical among many athletes also contributes to the spread of various contagious skin infections, according to Brian B. Adams, MD, dermatologist and preventive medicine physician from Cincinnati Ohio. He discussed skin conditions likely to result from skin-to-skin contact among athletes, and how to prevent the spread of such infections between players. "Outbreaks of ringworm, herpes and methicillin-resistant Staphylococcus aureus infection have occurred at the high school, collegiate and professional levels throughout the world," Dr. Adams said. "These skin conditions are highly contagious and can spread through sports teams quite quickly, especially if they are not immediately diagnosed and contained. That is why athletes need to be aware of these risks and how to spot the warning signs of a skin infection."

MRSA is particularly dangerous, and may initially appear only as a pimple, boil or abscess, with or without draining fluid or pus. MRSA lesions may be swollen, warm and tender to the touch, Dr. Adams said. He cited a recently published review of MRSA in athletes in which he reported that physical contact, shared facilities and equipment and poor hygiene were all major risk factors for MRSA infection, and that it was most common among football players. “Football players experience a variety of factors predisposing them to MRSA infections," said Dr. Adams. "These include skin injuries that can occur on the playing field, turf burns from artificial turf that can worsen skin trauma and even an athlete's ingrown toenail can lead to a MRSA infection. Some athletes are even carriers of the bacteria in their noses." He noted that proper treatment of MRSA

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requires quick diagnosis and treatment, thereby preventing the spread to other team members. He said that topical mupirocin can be effective in some patients, but those who are resistant to topical treatment may require an oral antibiotic. Viral infections are easily spread and very difficult to contain, Dr. Adams continued, specifically citing herpes simplex virus. Usually herpes presents as blisters and sores around the mouth, nose, genitals and buttocks, but it can appear anywhere on the body, especially on an athelete. Only early treatment can guarantee that the virus will not be spread to other team members. Typically, the athlete can return to practice and competition after four to five days of treatment, he said. "Herpes simplex is so common among wrestlers - where skin-to-skin contact is unavoidable - that the condition is termed herpes gladiatorum," he said. “Wrestlers who

Accurate birthmark identification determines treatment

health threat. “Over time, most infantile haemangiomas will disappear on their own, but there are instances where dermatologists will recommend treatment,” Dr. Friedlander noted. “For example, if an infantile haemangioma occurs around the eyes, it can obstruct and prevent normal visual development if left untreated, or, if they occur in the groin area, they can become inflamed and then cause pain to the child. Depending on their size, some facial birthmarks may leave behind a scar or saggy skin after they disappear. That is why it is often important for parents to consult a dermatologist as soon as their baby develops a birthmark, so it can be properly evaluated to determine if treatment is necessary,” she added. Infantile haemangiomas Dr. Friedlander continued by noting that a Dr. Friedlander noted that the most common broad facial haemangioma can be the first sign birthmarks are infantile haemangiomas. They of a serious disorder, termed PHACE syndrome, appear at birth or shortly thereafter and are which can suggest an underlying abnormality, small strawberry-shaped bumps or flat spots. including heart defects, eye abnormalities, Infantile haemangiomas grow during the first blood vessel or brain problems. Such two to six months of life, and a dermatologist haemangiomas require specialised evaluation can predict their growth by three to four and imaging, she said. months. Most infantile haemangiomas pose no Discussing treatment options for infantile haemangiomas, Dr. Friedlander cited several systemic spar with an infected partner have a one in three chance of steroids and intralesional steroid contracting this skin infection, so it is crucial that the virus is therapy that are often widely treated and athletes avoid competition during the period of used but can have adverse infection." clinical effects that must be Tinea corporis gladiatorum, or ringworm, is also common discussed with parents. Recently, among wrestlers. "Any athlete with skin-to-skin contact could the blood pressure-lowering develop ringworm, but the intensity of close contact and drug propranolol has shown exposed skin makes wrestling the highest risk sport for this efficacy in preventing growth, particular fungal infection,” Dr. Adams said. As with MRSA and and even shrinking, infantile herpes, early detection and treatment are essential in haemangiomas. But containing the spread of ringworm infection. Topical or oral propranolol is also associated antifungal medications are effective in clearing the infection, with adverse events that must be he said, but added that “there are no evidence-based closely monitored, she said. She recommendations as to how long athletes with ringworm also noted that topical should avoid competition.” medications and laser therapy Finally, tinea pedis or athlete’s foot is common among all are other options. athletes. "Athlete's foot can be treated successfully with one of the many over-the-counter topical antifungal creams, but there are also preventive steps that all athletes can take to reduce the Port-wine stains spread of this fungus," Dr. Adams said. "Moisture-wicking Dr. Firedlander noted that portsocks are a must, as cotton socks trap moisture and should not wine stains darken and thicken be worn by athletes. After working out or competing, athletes over time. They usually appear should shower immediately and make sure they wear flip flops on the face and are associated in the shower or locker room." with eye problems, including HILE ALMOST 10% of all infants have vascular birthmarks, specific treatment depends on accurate typing of the birthmark, according to an expert speaker at AAD. “There are several different types of birthmarks, so it is important to determine the type of birthmark before considering any possible treatments,” said dermatologist Sheila Fallon Friedlander, MD, professor of clinical paediatrics and medicine at the University of California San Diego (UCSD) and section chief of paediatric dermatology at Rady Children’s Hospital in San Diego.

glaucoma, and seisure disorders, she added. “Because port-wine stains grow and thicken over time and will not go away, many parents opt to treat them early when children are small,” she said. “While dermatologists have been using pulsed-dye lasers for decades to treat these types of birthmarks, different forms of laser therapy that penetrate more deeply - such as the Nd:YAG laser and the alexandrite longpulsed laser - also are now being used with much success.” Dr. Friedlander said that laser therapy begins during the first six to 12 months of life, with 6 to 8 treatments. She reported an ongoing investigation of oral rapamycin, for treating port-wine stains, in conjunction with laser therapy. She added that white birthmarks , though rarer than red birthmarks, appear as either flat or raised white spots on the skin. Usually harmless, some will enlarge and require removal, in which excision by CO2 laser is sometimes used, she said.

Brown birthmarks carry melanoma risk Finally, Dr. Friedlander discussed congenital nevus, a brow mole present at birth, that is the result of an increased number of melanocyte cells and which has the potential to develop into melanoma. Approximately 3% to 6% of very large congenital nevi can become cancerous, but these rates are debated, she said. Moles deemed high risk should be monitored closely or considered for surgical removal, she added. She noted that the café au lait birthmark is a light brown flat lesion that does not have clinical significance unless there are multiple such birthmarks or there is a very large spot. “If a patient has multiple café au lait birthmarks, they need to be evaluated by a dermatologist for other associated conditions. In particular, the health care provider needs to rule out neurofibromatosis, a genetically inherited disorder in which the nerve tissues grow tumours,” she said. “For patients who want to treat a cosmetically troublesome facial café au lait birthmark, various lasers exist that can be useful.”

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Dermatology reports

International Congress on Neuropathic Pain

Continued

Reports from the ICNP, Athens by Bruce Sylvester

Non-melanoma skin cancer in US -young people at special risk

ESEARCHERS AT AAD reported that the incidence of non-melanoma skin cancer in the United States is increasing, and that people there are not using sun protection adequately, in spite of substantial evidence that sun exposure is a preventable risk factor for the condition. Brett Coldiron, MD, dermatologist and assistant clinical professor of dermatology at the University of Cincinnati in Cincinnati, Ohio, reported new data identifying both the increase in nonmelanoma skin cancer and suggesting why there has been an increase in risk among young persons of developing this type of cancer. Dr. Coldiron reported that a recent analysis of Medicare claims showed that treatment of nonmelanoma skin cancers in the United States had almost doubled between 1994 and 2006, with more than 3.5 million new non-melanoma skin cancers estimated in 2006. And he reported that, in spite of proof that exposure to ultraviolet light is a preventable risk factor for skin cancer, attitudes about tanning remain unchanged for the same time period. He noted that the American Academy of Dermatology recommends application of a broadspectrum water-resistant sunscreen with a sun protection factor of at least 30 on all sun-exposed skin and use of protective clothing. The Academy also suggests that persons seek shade when appropriate, use extra caution around water, snow, and sand as they reflect the damaging rays of the sun, avoid tanning beds and get vitamin D safely, through a healthy diet that may include vitamin supplements. "As dermatologists, we know that it is hard to change behaviour, even in the face of proven scientific evidence," Dr. Coldiron said. "Attitudes about tanning are no different, as studies have shown that even though people know that overexposure to ultraviolet light can lead to skin cancer, they still tan. We need young people to realise that tanning for cosmetic reasons now will ultimately negatively affect their appearance later and even increase their risk for skin cancer."

New guideline released for treatment of diabetic nerve pain

HE AMERICAN ACADEMY of Neurology (AAN) has released a new guideline for the treatment of diabetic nerve pain. It was published in the recent online issue of the AAN journal Neurology. "When neuropathy strikes, it is painful and can disrupt sleep; because of this it can also lead to mood changes and lower quality of life," said lead author Vera Bril, MD, professor of medicine, University of Toronto in Ontario, Canada. "It is estimated that diabetic nerve

"It is estimated that diabetic nerve pain affects 16% of the more than 25 million people living with diabetes in the United States and is often unreported and more often untreated, with an estimated two out of five cases not receiving care." Dr. Vera Bril

pain affects 16% of the more than 25 million people living with diabetes in the United States and is often unreported and more often untreated, with an estimated two out of five cases not receiving care." The guideline cites evidence that the seizure drug pregabalin is an effective treatment for diabetic nerve pain. But the AAN emphasised that physicians should determine the drug’s therapeutic utility on a caseby-case basis. Also, the guideline says that some other treatments show treatment efficacy, including the seizure drugs gabapentin and valproate, the

antidepressants venlafaxine, duloxetine and amitriptyline, and painkillers such as opioids and capsaicin. Transcutaneous electric nerve stimulation (TENS) is also cited as a potentially effective treatment for diabetic nerve pain. "We were pleased to see that so many of these pain treatments had high-quality studies that support their use," said Dr. Bril. "Still, it is important that more research be done to show how well these treatments can be tolerated over time since diabetic nerve pain is a chronic condition that affects a person's quality of life and ability to function." The new guideline will be the foundation for the ongoing development of AAN tools to enable physicians to evaluate their care of nerve pain. The tolls will be released in 2012. This guideline is the joint product of the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation. The report has appeared in the April issue of the journal Muscle and Nerve from the American Association of Neuromuscular and Electrodiagnostic Medicine, and in the April issue of PM&R, the American Academy of Physical Medicine and Rehabilitation's scientific journal. Source: American Academy of Neurology

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Pain study by Bruce Sylvester

Massage has durable effect on lower back pain in randomised controlled trial

ESEARCHERS IN a randomised, controlled trial published recently in the Annals of Internal Medicine concluded that massage therapy, either structural or relaxation, eases chronic low back pain and improves back function.

"This is important because chronic back pain is among the most common reasons people see doctors and alternative practitioners, including massage therapists."

"We found that massage helps people with back pain to function even after six months," said trial leader Daniel C. Cherkin, PhD, a senior investigator at Group Health Research Institute, a Seattle-based, consumer-governed, nonprofit

health care system. “Better function” was defined as more able to work, provide self-care and be generally active. "This is important because chronic back pain is among the most common reasons people see doctors and alternative practitioners, including massage therapists," Dr. Cherkin added. "It's also a common cause of disability, absenteeism, and 'presenteeism,' when people are at work but can't perform well." The investigators enrolled 400 subjects reporting low back pain ("nonspecific," meaning with no identifiable cause ) for at least three months. They were randomised to one of three treatments: structural massage (identifying and focusing on specific painrelated "soft tissues" like muscles and ligaments), relaxation massage (“Swedish” massage), or usual care (most often medication-only). The massage subjects received hour-long massages weekly for ten weeks. At ten weeks, over one-third of massage subjects and only one in 25 usual care subjects reported that their back pain was much improved or eliminated. At ten weeks, a questionnaire showed that nearly twice as many massage patients as usual-

care patients were functioning significantly better than at the trial's outset. Patients in the massage groups spent fewer days in bed, were more active, and used less anti-inflammatory medication than did those with usual care. "As expected with most treatments, the benefits of massage declined over time," Dr. Cherkin said. "But at six months after the trial started, both types of massage were still associated with improved function."

"As expected with most treatments, the benefits of massage declined over time. But at six months after the trial started, both types of massage were still associated with improved function."

"We found the benefits of massage are about as strong as those reported for other effective treatments: medications, acupuncture, exercise, and yoga," Dr. Cherkin said. "And massage is at least as safe as other treatment options. So people who have persistent back pain may want to consider massage as an option." "The massage therapists assumed structural massage would prove more effective than relaxation massage," added Dr. Cherkin's colleague Karen J. Sherman, PhD, MPH, a senior investigator at Group Health Research Institute. "They were surprised when patients in the relaxation group got so much relief from their back pain." The National Center for Complementary and Alternative Medicine (NCCAM), part of the National Institutes of Health, funded this study.

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Undertreated pain management post-op benefits from innovative techniques

ESPITE NEW STANDARDS, guidelines, and educational efforts, acute pain after surgery continues to be undertreated worldwide, with up to 75% of surgical patients in the USA still failing to receive adequate post-op pain relief.1 The findings also reveal that chronic pain after surgery is a bigger problem than previously recognised, affecting up to half of patients undergoing common operations. However, new pain medications and techniques under development could help improve symptom relief for patients.

"Why there has been little progress in the treatment of acute postoperative pain is unclear, but the causes might be multifactoral, including the continued paucity of pain assessment and documentation...”

In the paper, Christopher L Wu and Srinivasa Raja from John Hopkins University and School of Medicine, Baltimore, USA review the progress made in treatments for postoperative pain over the past decade and stress that despite advances in pain management, a high percentage of patients continue to experience moderate-to-severe pain after surgery. Inadequate post surgical pain management is not just limited to adults, with a study from the USA reporting as many as 86% of children experiencing significant pain on the first day home after undergoing routine tonsillectomy. Recent research also shows that the development of chronic pain after surgery, known as persistent postsurgical pain [PPP], is a frequent outcome of surgery. As many as 30% of patients undergoing common operations

such as mastectomy, thoracotomy, hernia repair, and coronary artery bypass have to cope with PPP. They authors say: "Why there has been little progress in the treatment of acute postoperative pain is unclear, but the causes might be multifactoral, including the continued paucity of pain assessment and documentation, heightened awareness and increased number of audits or surveys leading to increased identification of undertreatment of pain…deficiencies in educational pain management programmes for health-care workers, underuse of effective analgesic techniques, and poor adherence to available guidelines." However, some interventional techniques have had a substantial impact on pain control over the past decade. In particular, regional analgesic techniques (such as epidural analgesia and peripheral nerve catheters using local anaesthetics) have been associated with significantly lower pain scores, earlier mobility, and reduced length of hospitalisation compared with the use of systemic opioids. Furthermore, such techniques eliminate the risk of addiction. Other promising interventions still under development include the transdermal patch for the patient-controlled delivery of pain medication providing a needle-free effective alternative to the intravenous pump; extended-release local anaesthetics to prolong the action of commonly used local anaesthetics; and disposable devices to allow infusion of local anaesthetics on an outpatient basis reducing the need for opioids and their adverse effects (nausea,

constipation, respiratory depression). They conclude: "Additional studies on predictors of postoperative pain and persistent postsurgical pain, efficacy of multimodal analgesic regimens [using more than one class of pain medication or technique], and growth of promising new technologies might lead to substantial gains in the treatment of acute postoperative pain and potential reduction in the development of persistent pain states [a not uncommon outcome of surgery]." For further information contact Professor Christopher L Wu, John Hopkins University and School of Medicine, Baltimore, USA. chwu@jhmi.edu Reference: 1. http://www.thelancet.com/journals/lancet/article/ PIIS0140-6736(11)60245-6/abstract

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Convenience1 of DROPS for patients with moderate to severe pain.

Now introducing, Tramadol Drops 100mg/ml, oral solution Convenience of Drops

Convenient option for

in patients with swallowing patients with swallowing 2 2 difficulties like the elderly difficulties . Ideal for: palliative care • Elderly patients2 for dose titration1 •

Treating Cancer pain3,4

•

A Useful alternative to

Tramadol - effective analgesic3 in treating Cancer pain3,4drugs5 opioid containing a useful alternative to opioid containing drugs5 Abbreviated Prescribing Information Tramadol 100 mg/ml oral drops, solution. Presentation: Tramadol drops are supplied as a 10 ml amber glass bottle with 1ml containing 100 mg of tramadol hydrochloride. Excipients: 1 ml contains 200 mg sucrose (see section 4.4). For a full list of recipients, see section 6.1. Indications: Treatment of moderate to severe pain. Dosage and administration: For oral administration. Should be diluted with water before administration, independent of meals. It is recommended to start with the lowest analgesically effective dose. Daily doses of 400 mg should not be exceeded, except in special clinical circumstances. Adults and adolescents above the age of 12 years: usual daily dose is 50 to 100 mg (20 to 40 drops), 3 to 4 times a day. Children from 12 to 14 years, the lowest dose should be used. For acute pain, an initial dose of 100 mg is usually necessary. For chronic pain, an initial dose of 50 mg is advised to be slowly increased to the final recommended dose every 2 to 3 days in order to reduce the incidence of adverse events. Below the age of 12 years tramadol drops are not suitable for children. Geriatric patients: No dose adjustment necessary in elderly patients up to 75 years without clinically manifest hepatic or renal insufficiency. Dosage interval should be extended according to the patients requirements in patients over 75 years as they may have prolonged elimination. Tramadol drops are not recommended in of severe renal and/ or severe hepatic insufficiency. Contraindications: Tramadol drops are contraindicated in hypersensitivity to tramadol or any of the excipients, in acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotropic medicinal products, in patients who are receiving MAO inhibitors or who have taken them within the last 14 days, in patients with epilepsy not adequately controlled by treatment, and for use in narcotic withdrawal treatment. Warnings and Special Precautions: Caution is recommended in opioid-dependent patients, patients with head injury, shock, reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure and in patients sensitive to opiates. The possibility of respiratory depression cannot be excluded if concomitantly administered with CNS depressant drugs or if the recommended dosage is significantly exceeded. Convulsions may occur even at the recommended doses risk in patients taking products that lowers the seizure threshold. The risk is increased if the upper daily dose limit (400 mg) is exceeded. Use in patients with epilepsy or those susceptible to seizures only if there are compelling circumstances. Tolerance, psychic and physical dependence may develop with long-term use. Short treatment periods are advised in patients with a tendency to drug abuse or dependence. Tramadol cannot

suppress morphine withdrawal symptoms and is not a suitable substitute in opioid-dependent patients. Not recommended in patients with fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency. Contains sucrose. Pregnancy and lactation: Tramadol crosses the placenta and is contraindicated in pregnancy due to inadequate safety evidence in human pregnancy. Very high dose animal studies revealed effects on organ development, ossification and neonatal mortality but no teratogenicity. No effect on uterine contractility when administered before or during birth may induce insignificant changes in neonatal respiratory rate. Chronic use during pregnancy may lead to neonatal withdrawal symptoms. Small amounts are secreted into breast milk therefore not recommended during breast-feeding. Interactions: Concurrent use ,with MAO inhibitors, CNS depressants including alcohol, carbamazepine (enzyme inducer), buprenorphine, nalbuphine, pentazocine, selective serotonin re-uptake inhibitors, tricyclic antidepressants, anti-psychotics and other seizure threshold-lowering medicinal products , coumarin derivatives (e.g. warfarin) and CYP3A4 inhibitors, such as ketoconazole and erythromycin. The pre- or postoperative ondansetron may increase the requirement of tramadol in patients with postoperative pain Undesirable effects: The most commonly reported adverse reactions are nausea and dizziness, headache, drowsiness, somnolence, constipation, dry mouth, vomiting, dyspepsia, abdominal pain, sweating, menopausal symptoms, fatigue, asthenia, and malaise occur commonly. Less commonly seen are toxic epidermal necrolysis (TEN) and Stevens-Johnson-syndrome (SJS), and cross reactivity with non steroidal anti-inflammatory drugs. Palpitation, tachycardia, postural hypotension or cardiovascular collapse may occur on intravenous administration or in physically stressed patients bradycardia and hypertension are rare. Anorexia, retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea, dermal reactions (e.g. pruritus, rash, urticaria) also occur less commonly. Rare side effects include: changes in appetite, increased liver enzymes, blurred vision, paraesthesia, tremor, respiratory depression, dyspnoea, worsening of asthma epileptiform convulsions, involuntary muscle contractions, muscle weakness, abnormal coordination, syncope, hypertonia and dysgeusia, micturition disorders , menstrual disorders, weight loss, allergic reactions, anaphylaxis, withdrawal reactions like agitation, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms may occur, psychic reactions like hallucinations, confusion, sleep disturbance, anxiety and nightmares occur rarely dependence, suicidal ideation, drug abuse addiction, panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms

(i.e. confusion, delusions, depersonalization, derealization, paranoia have also been seen with tramadol discontinuation. Overdose: Symptoms may include: miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest. The antidote for respiratory depression is naloxone. If convulsions occur, administer intravenous diazepam. Decontamination with activated charcoal or gastric lavage is only recommended within 2 hours after oral intoxication. Please refer to the Summary of Product Characteristics for detailed information. Legal Category: POM. Basic NHS Price: £3.50 per pack of 1 10ml bottle. Marketing Authorisation number: PL 12762/0453. Marketing Authorisation Holder: Goldshield Pharmaceuticals Ltd. NLA Tower, 12-16 Addiscombe Road, Croydon, CR0 0XT, UK. Date of Preparation of the Last Review: July 2011. Adverse events should be reported to the local regulatory authority. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Goldshield Medical. Information at 08700 70 30 33 or via e-mail to medicalinformation@goldshieldgroup.com See SmPC for further information before prescribing, particularly in relation to side-effects, precautions and contra-indications. References: 1. Support Care Cancer (2005) 13:5-17, The role of tramadol in cancer pain treatment- a review. 2. Administering drugs to patients with swallowing difficulties, Nursingtimes.net, 27th September,2005 VOL:101, Issue:39, Page no: 28, Heather Morris. 3. Drugs 46 (2): 313-340, 1993, Tramadol a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in acute and chronic pain states. 4. WHO Guidelines for Cancer Pain relief with a guide to opioid availability 2nd Editition 1996. 5. Dayer et al, The pharmacology of Tramadol, Drugs 47(suppl 1), 3-7. Job bag code:4

Respiratory report by Samuel Peters

Clinical guideline for diagnosis and treatment of COPD released by US medical associations

N AUGUST , four US medical associations released jointly a clinical practice guideline for diagnosing and treating stable chronic obstructive pulmonary disease (COPD). The groups include the American College of Physicians (ACP), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and European Respiratory Society (ERS).

"This clinical practice guideline aims to help clinicians to diagnose and manage stable COPD, prevent and treat exacerbations, reduce hospitalisations and deaths, and improve the quality of life of patients with COPD," said lead author Amir Qaseem, MD, FACP, PhD, Director of Clinical Policy, American College of Physicians. "It is important for patients with COPD to stop smoking and for physicians to help their patients to quit smoking." COPD appears mostly in cigarette smokers. Symptoms include chronic cough, wheezing, shortness of breath, or significant activity limitation. The clinical practice guideline includes the following recommendations: • Physicians should use spirometry to assess airflow obstruction in patients with

respiratory symptoms. "While targeted use of spirometry for diagnosis of airflow obstruction is beneficial for patients with respiratory symptoms, particularly dyspnoea, it does not appear to have an independent influence on the likelihood of quitting smoking or maintaining abstinence," noted Nicola A. Hanania, MD, MS, FCCP, Chair, Airways Disorders NetWork, American College of Chest Physicians. • Physicians should not use spirometry to screen for airflow obstruction in individuals with no respiratory symptoms. "The routine use of spirometry for patients without respiratory symptoms could lead to unnecessary testing, increased costs, unnecessary disease labeling, and the harms of long-term treatment with no known preventive effect on avoiding future symptoms," said Gerard Criner, MD, Professor of Medicine, Temple University, and past chair of the American Thoracic Society's Assembly on Clinical Problems. • Treatment with inhaled bronchodilators may be used by stable COPD patients with respiratory symptoms and FEV1 (forced expiratory volume in one second) between 60% and 80% predicted. • Treatment with inhaled bronchodilators should be used for stable COPD patients with respiratory symptoms and FEV1 less than 60% predicted. • Physicians should prescribe monotherapy with either longacting inhaled anticholinergics or long-acting inhaled beta agonists for symptomatic patients with COPD and FEV1 less than 60% predicted. Clinicians should base the choice of specific monotherapy on patient

preference, cost, and adverse effect profile. • Physicians may administer combination inhaled therapies (long acting inhaled anticholinergics, long-acting inhaled beta agonists, or inhaled corticosteroids) for symptomatic patients with stable COPD and FEV1 less than 60% predicted. • Physicians should prescribe pulmonary rehabilitation for symptomatic patients with an FEV1 less than 50% predicted. Clinicians may consider pulmonary rehabilitation for symptomatic or exercise-limited patients with an FEV1 greater than 50% predicted. • Physicians should prescribe continuous oxygen therapy in patients with COPD who have severe resting hypoxaemia. The guideline was published in August in the Annals of Internal Medicine.

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American College of Cardiology Reports from the ACC, New Orleans by Bruce Sylvester

ACC and the AHA issue consensus document for BP control in elderly

N APRIL, the American College of Cardiology (ACC) and the American Heart Association (AHA) released an expert consensus document to help clinicians address the risk of hypertension in older adults. "Adequate control of high blood pressure in the elderly can significantly reduce cardiovascular events and mortality, and is much more cost-effective than treating heart problems that result from uncontrolled hypertension," said Wilbert S. Aronow, MD, clinical professor of medicine at New York Medical College/Westchester Medical Center in Vahalla, New York, and one of the chairs of the ACC/AHA writing committee. "The real concern is that a majority of elderly people have suboptimal control of their blood pressure and until recently - many clinicians didn't treat hypertension in octogenarians because they

worried that doing so would increase mortality." The authors noted that 64% of older men and 78% of older women have high blood pressure, increasing their risk of heart failure, stroke, coronary artery disease and atrial fibrillation, as well as chronic kidney disease and diabetes mellitus. At age 80 and older, only one in three men and one in four women have adequate control of their blood pressure. Prior to 2008, most hypertension trials had upper age limits for enrollment, failing to provide age-specific findings. But in 2008, results from the Hypertension in the Very Elderly Trial (HYVET) were published. Dr. Aronow said that HYVET was the first study to show the clear benefits of anti-hypertensive therapy in people 80 years and older, including a 30% reduction in stroke, 23% reduction in cardiac death, 64% reduction in heart failure and 21% reduction in all-cause mortality. "HYVET was the main impetus for developing this consensus document, which is designed to provide the medical community with systematic recommendations to lower blood pressure in older adults," said. Dr. Aronow. "Treating hypertension in the elderly is particularly challenging because they usually have several health problems and a greater prevalence of cardiovascular risk factors and cardiac events. There also needs to be greater vigilance to avoid treatment-related side effects such as electrolyte disturbances, renal dysfunction, and excessive orthostatic blood pressure decline." Consensus recommendations in the ACC/AHA consensus document include: • There has been uncertainty about the appropriate

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•

therapeutic target for patients ≥80 years of age. Levels of less than 140/90mmHg in persons 65-79 years and a systolic blood pressure between 140 and 145mmHg in persons 80 years and older (if tolerated) were identified; hypertension in older adults is usually characterised by an elevated systolic blood pressure and a normal or low diastolic BP due to age-associated stiffening of the large arteries. Angiotensin converting enzyme (ACE) inhibitors, beta blockers, angiotensin receptor blockers, diuretics and calcium channel blockers are all effective in lowering blood pressure and reducing cardiovascular outcomes among the elderly; clinicians should select medications based on efficacy, tolerability, specific comorbidities, and cost. For example, if someone has had a heart attack, they should be started on a beta blocker and an ACE inhibitor. Initiation of antihypertensive drugs in this population should generally be at the lowest dose with gradual increments as tolerated. There should be routine monitoring of blood pressure in this population, including measuring blood pressure in the standing position. Lifestyle changes to prevent and treat hypertension among older adults should be encouraged. These include regular physical activity, restriction of salt, weight control, smoking cessation and avoiding excessive alcohol intake (more than two drinks for men and one drink for women)

This ACC/AHA expert consensus document was developed in collaboration with the American Academy of Neurology (AAN), the American Geriatrics Society (AGS), the American Society of Hypertension (ASH), the American Society of Nephrology (ASN), the American Society for Preventive Cardiology (ASPC), the Association of Black Cardiologists (ABC), and the European Society of Hypertension (ESH.

It is posted on the ACC www.cardiosource.org and AHA www.heart.org web sites.

Cardiologists not always accurate in interpreting ECG results for young athletes

AEDIATRIC CARDIOLOGISTS are prone to misinterpreting electrocardiograms when using the results to determine whether young athletes have heart defects that could make exercising perilous, according to a new study. This is the first research to examine the acumen of paediatric cardiologists from several healthcare institutions in using ECGs to detect rare heart conditions associated with sudden cardiac death.

"An ECG doesn't always pick up the abnormalities that may predispose someone to sudden cardiac death." Dr. Allison Hill

Public outcries about sudden cardiac deaths among athletes have already prompted some European countries to require that young athletes undergo heart exams via ECG before they participate in sports. Even though the number of sudden cardiac deaths among young U.S. athletes is low - an estimated 76 per year some people have suggested that athletes here should also receive mandatory ECGs so that those vulnerable to sudden cardiac death could be warned not to play sports. The authors of the new research disagree. "An ECG doesn't always pick up the abnormalities that may predispose someone to sudden cardiac death," said Allison Hill, MD, the study's first author. "And this exam can be difficult to interpret, even if the person reading the scan is a paediatric cardiologist." Hill recently finished her paediatric residency at Packard Children's Hospital and is now a paediatric cardiology fellow at Children's Hospital Boston. In the new study, which will be published online in the Journal of Pediatrics, 53 members

of the Western Society of Pediatric Cardiology were asked to interpret a set of 18 ECG exams, some from healthy athletes and some from those with heart defects. The physicians, who had an average of five to 15 years of experience in their field, accurately diagnosed the heart conditions only 67% of the time. They correctly permitted sport participation for healthy individuals 74% of the time, and correctly restricted sport participation for those with cardiac defects 81% of the time. "As athletes' hearts grow stronger, they undergo some changes that make it very difficult to tell: Is this a well-trained athlete or does this person have some underlying disorder that may predispose them to sudden cardiac death?" Hill said. A fit heart tends to grow somewhat larger and beat more slowly, which can make it look similar on an ECG to a defective heart vulnerable to sudden cardiac death. This similarity could lead to unnecessary exclusion of healthy young people from sport participation. Conversely, some young athletes who are predisposed to sudden cardiac death may be given a clean bill of health based on a flawed ECG interpretation. "We need to be careful about giving a false sense of security to families, parents or an entire community if we have an ECG that's normal," Hill said. "It's important to know that it's not a perfect test." The physicians' accuracy at interpreting ECGs varied depending on what heart defect they were looking at. They were most accurate at picking up long QT syndrome and myocarditis, showing 98% and 90% accuracy at restricting sport participation for these two conditions. In contrast, they correctly restricted sport participation for patients with hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome and pulmonary arterial hypertension 80%, 64% and 38% of the time, respectively. (The poor result for pulmonary arterial hypertension may be due to the fact that it is much rarer than the other diagnoses, occurring in 30-50 people per million, whereas most of the other diagnoses are seen at a rates between one in 10,000 and one in 100 people.)

The new results dovetail with the current American Heart Association position on presport ECGs, which recommends against routine use of the exams because of the large number of athletes in the United States, the low frequency of diseases leading to sudden cardiac death, the low rate of sudden cardiac death itself and the frequent false-positives that could unjustly exclude healthy individuals from sport participation. The AHA instead recommends a thorough history and physical exam every two years for young athletes. A different Stanford study on ECGs for athletes, published in 2010, suggested ECGs for young athletes would be cost-effective. However, that study started from the assumption that ECGs would all be interpreted accurately, said cardiologist Euan Ashley, MD, who led the cost-effectiveness research. If the United States does start instituting screening programmes, Hill and her colleagues suggest that there is a need to ensure the

"We need to be careful about giving a false sense of security to families, parents or an entire community if we have an ECG that's normal." Dr. Allison Hill

physicians reading these ECGs are trained appropriately, which would add to the total load of information that paediatric cardiologists must already learn during their three-year training. It would also be important for physicians to use the proper normal values when evaluating these scans. Currently, there is not good consensus on what constitutes "normal" for a trained athlete's heart, said co-author Anne Dubin MD, associate professor of paediatric cardiology, adding that data from such individuals exists but has not been widely shared.

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European Heart Rythmn Association meeting by Peter Mas-Mollinedo

Adding CRT to CABG boosts heart failure outcomes

MPLANTING A CARDIAC resynchronisation therapy (CRT) device at the time of coronary artery bypass grafting (CAGB) in patients with ischaemic heart failure improves outcomes over CABG alone, a small, randomised trial showed. The addition of CRT improved left ventricular systolic function, reduced signs of dyssynchrony, and ultimately reduced mortality through 18 months of follow-up (P<0.05 for all), according to Alexander Romanov, MD, of the Novosibirsk State Research Institute of Circulation Pathology in Russia. Also, patients who received CRT had significantly greater improvements in NYHA functional class, six-minute walk test, and quality of life (P<0.05 for all), Romanov reported at EUROPACE, the meeting of the European Heart Rhythm Association. "Our data demonstrate that we don't need to wait if patients have indications for surgery and indications for CRT," he said. "We need to do it concomitantly." In a previous study of patients with ischaemic heart failure, those who had left ventricular dyssynchrony before CABG tended to have dyssynchrony after surgery, showing that CABG alone was not sufficient to resynchronise the left ventricular contraction pattern in most patients, according to Romanov.

Post-CABG dyssynchrony was associated with poorer long-term outcomes. To see whether adding epicardial CRT at the time of CABG improved outcomes, Romanov and his colleagues randomised 178 consecutive patients with severe ischaemic heart failure (NYHA class III or IV) and left ventricular dyssynchrony to CABG alone or CABG plus CRT at the time of surgery. All of the patients had indications for both CABG and CRT. The study was conducted at three centres one each in Russia, Poland, and Slovenia. Dyssynchrony was defined as the presence of at least one of the following criteria: a QRS duration greater than 120 milliseconds (ms), an aortic pre-ejection delay greater than 140ms, an interventricular mechanical delay greater than 40ms, delayed activation of the posterolateral left ventricular wall, and tissue tracking and tissue synchronisation image on tissue Doppler imaging. The patients in the two groups were well matched at baseline, with a mean age of 62.8, a mean left ventricular ejection fraction of 29%, and a mean QRS duration of 139ms. Short-term postoperative outcomes were better in the group that received CRT, illustrated by a shorter average stay in the intensive care unit (2.5 versus 3.9 days) and a better cardiac index on the second day after the operation (P<0.001 for both). Long-term outcomes through an average follow-up of 18.4 months were better in the patients who received CRT as well. In the CABG alone group, left ventricular ejection fraction improved slightly by three months but then returned to baseline levels. In the CABG plus CRT group, ejection fraction increased through about six months and then leveled out. Thus, at 18 months, ejection fraction was significantly greater in the CABG plus CRT group (42% versus 28%, P=0.0001).

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Measures of left ventricular dyssynchrony on tissue Doppler imaging -- which was associated with all-cause death and heart failure hospitalisation (HR 2.60, 95% CI 1.20 to 5.75) improved more in the CABG plus CRT group. Through follow-up, there were 32 deaths overall. Four of the five that occurred in the early postoperative period were in the CABG alone group. One patient died because of ventricular fibrillation four days after the operation and three patients died because of progression of heart failure.

Long-term outcomes through an average follow-up of 18.4 months were better in the patients who received CRT as well.

One patient died of postoperative MI in the CABG plus CRT group. During the entire follow-up period, the mortality rate was significantly higher in the CABG alone group (26.4% versus 9.9%, P=0.006). All but three of the observed deaths were cardiac - 16 pump failure deaths, 12 sudden cardiac deaths, and one death resulting from a cardiac procedure. Three-quarters of the sudden cardiac deaths occurred in the patients who did not receive a CRT device. Disclosure: Romanov reported receiving speaking honoraria from Medtronic and Biosense Webster. Reference: Romanov A, et al "Analysis of mortality events in ischaemic heart failure patients after coronary artery bypass grafting and concomitant cardiac resynchronisation therapy: results from a multicenter study" EUROPACE 2011; Abstract 125

European Medicines Agency

highlights

by Gary Finnegan

MEP objects to appointment of medicines expert

BITTER WAR OF words has broken out between the European Medicines Agency and a French MEP over the role of a Belgian scientist who is accused of playing down the risks associated with an appetite suppressant. The row dates back to a medicine safety assessment written in 1994 by Dr. Xavier Kurz, who is now an EMA pharmacovigilance advisor. The report examined whether isomeride increased the risk of cardiac events and was prepared by Dr. Kurz while he worked at a university and provided part-time expert advice to the Belgian medicines authorities. Gérard Bapt, a French socialist MEP, claims that Dr. Kurz “minimised and contested” aortic valve deficiencies in patients who had taken the anti-obesity drug which has been the subject of legal actions in France and the US amid claims of cardiac adverse events. These claims have been disputed given the difficulty in ascribing a causal link between a drug and heart problems in obese patients who are typically at heightened risk of cardiac events and who often take several medicines at once. France has for months been gripped by a separate drug safety scandal which centres on Mediator, a diabetes drug which was widely used off-label as a weight loss product. French authorities withdrew Mediator in 2009 following concerns that it could have been linked to between 500 and 2,000 deaths since the 1970s – a charge the manufacturer contested – pushing the issue of medicines’ safety to the top of the news agenda. The isomeride story has made the headlines in France partly thanks to the ongoing attention given to the Mediator case. Gérard Bapt MEP is President of the French parliamentary mission investigating Mediator. In Brussels, EU Health Commissioner John Dalli is caught in the middle of the row over Dr. Kurz’s role at the EMA. It was to Dalli that Bapt, the French MEP, addressed his letter which questioned the fitness of Dr. Kurz to work at the EU medicines watchdog. EMA acting executive director, Andreas

Potts, wrote to Dalli to defend Dr. Kurz, saying the controversial 1994 report has ultimately served to improve scientific understanding of the risks of appetite suppressants. “I would like to reiterate my absolute confidence in Dr. Kurz’s scientific and personal integrity. He has been a most valuable expert in pharmacovigilance and pharmacoepidemi-ology, both prior to starting working at the European Medicines Agency and since joining the Agency. His contribution to European public health is highly appreciated throughout the European regulatory network,” Potts wrote. The appointment of experts is typically decided by the EMA, with the European Commission rubber-stamping the Agency’s choice unless it has specific concerns about the suitability of the candidate. Thanks to the intervention of Gérard Bapt MEP, the EMA’s personnel matters are now political.

New EU rules on fake medicines The final text of the new European directive on falsified medicines has been published, after years of wrangling between MEPs, the European Commission and national health authorities. The new law covers products that pass themselves off as legitimate medicines, as well as ingredients of low quality or where the source has not been identified. It is designed to prevent falsified medicines from entering the legal supply chain and reaching patients, and includes a raft of harmonised safety measures. These include mandatory features on medicines packaging, a tougher inspection regime for manufacturers, a requirement for manufacturers and distributors to report suspicions of fake pharmaceuticals, and an obligatory logo for websites of legally operating online pharmacies with a link to official national registries. The first draft of the directive was published in 2008 and it officially came into force on July 21, 2011. However, member states have until January 2013 to apply the new rules.

New drugs approved The EMA’s Committee for Medical Products for Human Use (CHMP) has given the green light to a number of new medicines: Dexdor (dexmedetomidine), from Orion Corporation, intended for sedation of adult intensive care unit (ICU) patients. Dexdor allows more flexibility in the ICU setting for patients who do not require deep sedation and has shown the additional advantage of reducing the time for extubation compared with the standard of care. Incivo (telaprevir), from Janssen-Cilag International N.V., intended for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease. Telaprevir belongs to a new class of medicines for the treatment of chronic hepatitis that can directly inhibit viral replication in infected host cells which can lead to the eradication of the virus, and thus effectively to a cure of chronic hepatitis C. Mercaptopurine Nova Laboratories (mercaptopurine monohydrate), an orphan medicine from Nova Laboratories Ltd, intended for the treatment of acute lymphoblastic leukaemia in adults, adolescents and children. Plenadren (hydrocortisone), an orphan medicine from DuoCort Pharma AB, intended for the treatment of adrenal insufficiency in adults. Vyndaqel (tafamidis), from Pfizer Specialty UK Ltd, an orphan medicine intended for the treatment of transthyretin amyloidosis in adult patients with symptomatic polyneuropathy, a severe, progressive orphan disease. Vyndaqel is the first oral pharmacological treatment recommended for this rare disease. Zytiga (abiraterone acetate), from JanssenCilag International N.V., intended in combination with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxelbased chemotherapy regimen.

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Journal reviews by Bruce Sylvester

Reporting from some of the latest articles in

the medical community eradicate hepatitis C infection in a majority of patients." Telaprevir is a protease inhibitor that shuts down the enzyme that processes the protein product of the viral genome, after HCV infects human cells. The drug is effective against HCV genotype 1, the predominant genotype in the USA, Europe, Japan and elsewhere. In the ADVANCE trial, 1,088 untreated patients diagnosed with HCV genotype 1 were assigned to one of three treatment arms: standard therapy for 48 weeks, or telaprevir combined with standard therapy for eight or for 12 weeks, followed by standard therapy alone for total treatment duration of either 24 or 48 weeks. The invstigators reported that sustained virologic response occurred in significantly more patients receiving 12 weeks (75%) or 8 weeks (69%) of telaprevir therapy compared to standard therapy alone (44%). In all, 58% of telaprevir-treated patients received 24 weeks of total treatment.

www.nejm.org

Telaprevir-based regimen achieves breakthrough in treatment of hepatitis C

ATIENTS TREATED WITH telaprevir (Incivek) have achieved dramatic improvement in the most common form of hepatitis C infection, researchers report. The findings, which appeared in the recent edition of the NEJM, led to approval of the agent for patient use by the U.S. Food and Drug Administration (FDA) on May 23. Results of the ADVANCE trial showed that telaprevir combined with standard therapy (pegylated-interferon and ribavirin) cured 75% of patients, compared with 44% of those who received standard therapy alone. Almost 60% of telaprevir-treated patients who had undetectable viral levels at weeks four and 12 of treatment were eligible to receive 24 weeks of total treatment, and approximately 90 of these patients were cured. Telaprevir represents a, "quantum leap forward into a new era of hepatitis C therapy," said Dr. Jacobson, chief of the Division of Gastroenterology and Hepatology and the Vincent Astor Distinguished Professor of Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, in New York, NY. "This agent directly targets the virus and, together with the also recently introduced protease inhibitor boceprevir, is the first of a coming wave of new treatments that will help

In the ADVANCE trial, 1,088 untreated patients diagnosed with HCV genotype 1 were assigned to one of three treatment arms. Dr. Jacobson noted that there were significant benefits of telaprevir in groups of patients who do not generally respond well to standard therapy. For example, 62% of AfricanAmerican subjects achieved a viral cure with the telaprevir-based regimen, compared with 25% of African-Americans treated with standard therapy. In addition, 62% of patients with advanced liver cirrhosis achieved a viral cure with telaprevir compared with 33% of similar patients on standard therapy. "We have closed the gap on cure in these populations," he said. "Telaprevir is not the end of the story. There are many exciting drugs being evaluated," Dr. Jacobson added. "Our most cherished goal is to cure HCV in all patients with a cocktail of fastacting and well-tolerated drugs that have direct action against the virus or, in some cases, may target factors in the host that contribute to HCV replication or its consequent liver disease. Many lives will be saved." Telaprevir was developed by Vertex

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Pharmaceuticals Incorporated in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. Vertex provided funding for the study.

www.jama.ama-assn.org

Intensive-dose statin therapy linked to increased risk of diabetes

META- ANALYSIS OF data from previously published studies suggests that intensive-dose statin therapy increases the risk of new-onset diabetes compared with moderate-dose therapy. The findings appeared in a recent issue of JAMA. As background, the authors noted that, compared with placebo, statin therapy significantly reduces cardiovascular events among individuals with and without a history of diabetes mellitus. But, several trials comparing intensive- to moderate-dose statin therapy have suggested an excess risk of new diabetes among those treated with intensive statin regimens. "Given the cardiovascular benefits of statins and the likely increasing use of intensive statin regimens, it is important to quantify any potential long-term risks to enable physicians and patients to make informed choices," the authors wrote. Conducting a meta-analysis of published and unpublished findings from relevant clinical trials, David Preiss, MRCP, of the University of Glasgow, UK and colleagues evaluated the data for associations of intensive-dose statin therapy vs. moderate-dose therapy with the development of diabetes and the occurrence of major cardiovascular events. They identified five statin trials that met criteria for inclusion in the meta-analysis. The five trials provided data on 32,752 nondiabetic participants, with an average follow-up of 4.9 years. During follow-up, 2,749 participants (8.4%) developed diabetes (1,449 of whom were assigned intensive-dose therapy, 1,300 assigned moderate-dose therapy), and 6,684 (20.4%) experienced a major cardiovascular event (3,134 assigned intensive-dose therapy, 3,550 assigned moderate-dose therapy). There were 149 more cases of incident diabetes in participants assigned to intensive statin treatment than in those receiving moderate therapy and 416 fewer patients with cardiovascular events who received intensive-

dose therapy. Subsequent analysis of the data showed that use of intensive-dose statin therapy compared with moderate-dose statin therapy was associated with a higher incidence of newonset diabetes. But intensive statin therapy was associated with fewer major cardiovascular events. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. "Our findings suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy," the authors wrote. "In conclusion, this meta-analysis extends earlier findings of an increased incidence of diabetes with statin therapy by providing evidence of a dose-dependent association."

BMJ

www.bmj.org

Obesity contributes significantly to premature mortality in nonsmoking women

BESITY CONTRIBUTES significantly to premature death among women who have never smoked, especially those low income groups, researchers reported recently in the BMJ. Even though prior research has shown conclusively that smoking leads to premature death and health inequalities, it had not been established which causes of death are related to the social position of women who have never smoked, the authors noted. Dr. Laurence Gruer from NHS Health Scotland, reviewed the cases of 3,613 women who had never smoked. These women participated in a study of over 15,000 adults who were recruited in Scotland between 1972 and 1976 when aged 45-64, and who were followed until death. Dr. Gruer and colleagues grouped the participants by occupational class (1 & 2, 3 non manual, 3 manual, and 4 & 5) and by weight (normal weight, overweight, moderately obese and severely obese). During the 28 years of follow-up, half the women died, including 916 (51%) from diseases of the heart and circulation and 487 (27%) from cancer. The investigators found that women in the

lower occupational groups were more likely to die of diseases of the heart and circulation, but not of cancer. They were also more likely to be severely obese and those who were severely obese had the highest death rates. They also found that, compared with the smokers in the overall study, the women who never smoked were much more likely to be overweight or obese. They concluded that this suggests that high smoking rates 35 years ago probably concealed the true extent of obesity in non-smoking women, and that the decline in smoking rates in recent decades may have contributed to the increase in overweight and obesity. The authors noted that women who never smoke and are not obese have relatively low mortality rates regardless of their social position. In the accompanying editorial, Professor Johan Mackenbach from the Erasmus Medical Center in Rotterdam, wrote that the study is welcome, "but it is important not to forget that smoking is a much stronger risk factor for mortality than most other risk factors, including obesity." He concluded that "inequalities in mortality persist among those who have never smoked, partly because obesity takes over the role of smoking, but they persist at a much lower level, and that is good news for whoever wants to reduce health inequalities."

www.thelancet.com

Bivalirudin ups survival in heart-attack patients

INDINGS from the HORIZONS-AMI trial show that, three years after treatment, bivalirudin enhances survival compared to heparin plus a glycoprotein (GP) IIb/IIIa inhibitor in heart attack patients undergoing angioplasty. Also a drug-eluting stent (paclitaxel) was more effective than a baremetal stent, with equivalent safety. Final three-year results of the trial were published in the recent issue of The Lancet. HORIZONS AMI (Harmonizing Outcomes with revascularisation and Stents in Acute Myocardial Infarction) included 3,602 patients presenting with a heart attack to hospitals in 11 countries. More than 120 national and international interventional cardiology centres participated in the trial. After three years, treatment with bivalirudin

alone compared to heparin plus a GP IIb/IIIa inhibitor resulted in significantly reduced rates of all-cause mortality (5.9% vs. 7.7%), cardiac mortality (2.9% vs. 5.1%), reinfarction (6.2% vs. 8.2%) and major bleeding not related to bypass graft surgery (6.9% vs. 10.5%). The investigators reported no significant differences in the incidence of ischaemia-driven target vessel revascularisation, stent thrombosis, stroke, or composite adverse events. They also reported that, after three years, implantation of a paclitaxel-eluting stent compared to a bare-metal stent resulted in significantly lower rates of ischaemia-driven target lesion revascularisation (9.4% vs. 15.1%) with no significant differences in the rates of death, reinfarction, stroke, or stent thrombosis. "The results at three years demonstrate that use of bivalirudin alone, as opposed to a combination of heparin and a GP IIb/IIIa inhibitor, can save lives. The reported reduction in all-cause mortality seen in the trial equates to 18 lives saved per 1,000 patients treated with bivalirudin," said lead investigator Gregg W. Stone, MD, Professor of Medicine at Columbia University College of Physicians and Surgeons, Director of Cardiovascular Research and Education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian Hospital/Columbia University Medical Center in New York, NY, and Co-Director of the Medical Research and Education Division at the Cardiovascular Research Foundation (CRF). "Additionally, results of the trial showed that patients who received a paclitaxel-eluting stent had a 40% reduction in risk of ischaemia-driven target lesion revascularisation after three years compared with those patients given a baremetal stent," he added. The authors noted that prior research with drug-eluting stents had focused on use in patients with stable or unstable chest pain. HORIZONS AMI is the largest study to focus on the appropriate use of anticoagulation medications and drug-eluting stents in patients experiencing the most dangerous form of heart attack (ST-elevation myocardial infarction). The study was sponsored by the Cardiovascular Research Foundation, with research grant support from Boston Scientific Corporation and The Medicines Company. Sources: New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College, JAMA, BMJ, Cardiovascular Research Foundation .

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Medical news from around the world by Gary Finnegan

World Health Matters AUSTRALIA Revealed: factors in vaginal birth after caesarean PRIVATE HEALTH INSURANCE, induction, cervical ripening agents, local guidelines and scoring systems are just some of the factors which influence the prevalence of vaginal birth after a previous caesarean section. That’s according to a review of 700,000 women in hundreds of hospitals across 13 countries, published in the Journal of Advanced Nursing. Researchers from the Faculty of Nursing, Midwifery and Health at the University of Technology, Sydney, Australia, were keen to see if clinical and non-clinical interventions increased the uptake and/or success of vaginal births after caesarean sections (VBAC). Their findings, rather than pin-pointing a single determinant explaining why some countries have higher rates of VBAC than others, turned up a complex array of reasons behind caesarean rates. “Many women who have had caesarean sections opt for the same procedure with their next pregnancy. Caesarean rates have increased around the world in the past two decades and much of this increase is due to women who have had previous caesareans,” says lead author Christine Catling-Paull. “Research shows that only 33% of women in the UK will have a VBAC and in Australia the rate is even lower at just under 17%. However, another study from the USA shows that 73% of women who had a caesarean went on to have a successful vaginal delivery.” The review of non-clinical factors comprised 34 papers published between 1984 and 2007, based on studies conducted in the USA, Canada, the UK, Australia, France, China, Ireland, Israel, Jordan, Scotland, Singapore, Switzerland and South Africa. They found that guidelines, audit and feedback, and the attitudes and characteristics of individual clinicians have an impact on VBAC rates. Local guideline changes appear to have a greater effect on practice than guidelines that

are developed and distributed on a large scale, possibly because they are more likely to be driven and owned by local clinicians, according to the researchers. There is inconsistent evidence that having private health insurance may be a barrier to a successful VBAC, the researchers said, reporting mixed conclusions from the large data set included in the review. The review of clinical factors comprised 27 papers published between 1989 and 2008 and found that VBACs tend to be less successful if they are induced using artificial rupture of membranes, prostaglandins, oxytocin infusion and various combinations of these methods. It also showed that cervical ripening agents, such as prostaglandins and transcervical Foley catheters, may result in a lower VBAC rate compared with women who go into labour spontaneously. Women who have X-ray pelvimetry have a reduced uptake of VBAC and higher caesarean section rates, according to the study, leading the researchers to advise against this practice. Local guidelines and evidence-based decisionmaking are required if the uptake and success of VBACs is to be increased, they concluded.

SOUTH KOREA Simple test boosts lung cancer outcomes A RELATIVELY SIMPLE and inexpensive method can be used to determine whether a lung cancer patient is a candidate for crizotinib therapy, according to new research. The study, published in the Journal of Thoracic Oncology, could help identify patients with anaplastic lymphoma kinase (ALK) rearrangement which is seen in certain forms of non-small cell lung cancer. ALK is an enzyme which plays an important role in the development of the brain. Lung cancer patients with ALK rearrangement have been found to respond well to crizotinib, an ALK inhibitor currently in clinical trials. Fluorescence in situ hybridization (FISH) has

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been considered the gold standard method for detecting ALK rearrangement, but clinicians say it is imperfect and expensive. “FISH requires a fluorescence microscope, and the signals are labile and rapidly fade over time,” researchers wrote in the study, led by Dr. Jin-Haeng Chung of Seoul National University Bundang Hospital in South Korea.

“FISH requires a fluorescence microscope, and the signals are labile and rapidly fade over time.” Dr. Jin-Haeng Chung

Researchers compared ALK rearrangement assessments using FISH and a newly developed method called chromogenic in situ hybridisation (CISH). CISH allows detection of gene copy status using a conventional peroxidase-base reaction and standard bright field light microscope – a significantly cheaper piece of kit. Out of a total 465 non-small cell lung cancer samples, ALK rearrangement was assessed using CISH in 449 patients (96.6%) and ALK rearrangement was identified in 18 patients (4%). Using FISH, ALK rearrangement was assessed in 453 patients (97.4%) and ALK rearrangement was identified in 19 patients (4.2%). Among these cases, 443 cases (95.3%) had results matching the corresponding FISH results: 17 rearranged, 425 wild types, and one discordant case. “There was high concordance in the assessment of ALK gene rearrangement between FISH and CISH techniques,” researchers wrote.

Crizotinib is still in the final phases of clinical trials but research presented at the American Society of Clinical Oncology (ASCO) has shown that it may prolong survival and “fundamentally alter the natural history” of ALK-positive nonsmall cell lung cancer. Coupled with a relatively cheap and straightforward test, it could help improve the prognosis for lung cancer patients.

CANADA Clearer guidelines cut antibiotic use HEALTH PROFESSIONALS IN Quebec, Canada, have cut down on overuse of antibiotics by publishing simple, easy-to-use guidelines for health professionals. The guidelines are concise but provide an overview of best practice in treating different categories of patient, including separate information for treating adults and children, as well as specific guidance on caring for patients with diseases such as COPD, pneumonia and urinary tract infections.

“Simple, short, easy-to-use guidelines have an impact on physicians when they are readily available.” Dr. Karl Weiss

Antibiotic overuse and resistance have emerged as major threats during the past two decades. Following an outbreak of Clostridium difficile infections, which often result from antibiotic use, healthcare professionals in Quebec, Canada targeted physicians and pharmacists with an education campaign that reduced outpatient antibiotic use, according to a study published in Clinical Infectious Diseases. The Quebec Minister of Health and the Quebec Medication Council collaborated with designated physicians and pharmacists to develop the guidelines in an effort to improve prescribing practices. First issued in January 2005, the guidelines emphasised proper antibiotic use, including not prescribing antibiotics when viral infections were suspected and selecting the shortest

possible duration of treatment. Approximately 30,000 printed copies of the original recommendations were distributed to all physicians and pharmacists in Quebec. An additional 193,500 copies were downloaded from the Medication Council's website. During the year after the guidelines were initially distributed, the number of outpatient antibiotic prescriptions in Quebec decreased 4.2%. In other Canadian provinces, the number of these prescriptions increased 6.5% during the same period. According to study author Dr. Karl Weiss of the University of Montreal, the Quebec experience shows what can be done through collaboration between health authorities, pharmacists and doctors. “It is possible to decrease antibiotic consumption when physicians, pharmacists, state governments, etc., are working together for a common goal. This is the key to success: having everybody involved and speaking with a common voice.” He said “simple, short, easy-to-use guidelines have an impact on physicians when they are readily available”, adding that the web plays a key role in getting the message to frontline staff. “With handheld electronic devices available for all healthcare professionals, these downloadable guidelines can be accessed and used at any time and any circumstance,” said Dr. Weiss.

ISRAEL New prevalence method reveals Parkinson’s rise A NEW METHOD for measuring the prevalence of Parkinson’s disease has revealed a sharp increase in the estimated number of people affected by the condition in Israel. In the a new study, published in the inaugural issue of the Journal of Parkinson's Disease, Israeli researchers report that by tracking pharmacy purchases of anti-Parkinson drugs they could estimate the number of Parkinson's disease (PD) cases in a large population. The study identified a sharp rise in PD prevalence from 170 per 100,000 of population in 2000 to 256 per 100,000 in 2007 in Israel. The finding sparked calls for further investigation into whether this somewhat crude yardstick for estimating prevalence could provide a more accurate picture than existing methods.

Surprisingly, much of the world lacks accurate figures for the percentage of the population with PD and the rate of occurrence of new cases. Reliable estimates using epidemiological population studies are essential to identify risk factors for developing the disease, and thereby reduce risk. They are also important for planning how many patients with the disease may need treatment by health services. “Our proposed algorithm may be used as a reliable and low-cost tool to establish PD cohorts for epidemiological studies,” said lead investigator Nir Giladi, MD, Chairman, Department of Neurology, Tel Aviv Sourasky Medical Center, and Associate Professor, Sackler School of Medicine, Tel Aviv University. “Our findings of prevalence and incidence are higher than expected, and a rising number

“Our proposed algorithm may be used as a reliable and lowcost tool to establish PD cohorts for epidemiological studies.” Dr. Nir Giladi

of PD patients in Israel reflect the growing burden of PD morbidity on Israeli health and social systems, and should be the base for national resource planning for the future.” Dr. Giladi’s refined drug-driven algorithm assessed PD patients at three certainty levels – definite, probable, and possible – based on the fact that PD therapy is chronic and generally involves an increasing number of drug-types and dosages as the disease progresses. Thus, those levels of accuracy were assigned based on specific combinations of categories of four factors: (a) PD drug types used; (b) age at first PD drug purchase (c) follow-up period; and (d) PD drug purchase intensity - number and continuity of purchases. Using the pharmacy records of over 1.8 million people who were members of the Maccabi Healthcare Service (MHS) in Israel (about 25% of the total population), researchers found 499,629 PD drug prescriptions were dispensed to 18,546 MHS members between January 1, 1998 and December 31, 2008. Researchers say the method could be adopted by other countries where detailed pharmacy dispensing information is available.

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FDA highlights by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs DMARDs appear to reduce risk of diabetes in patients with rheumatoid arthritis or psoriasis

ESULTS FROM A RETROSPECTIVE study of nearly 14,000 patients with rheumatoid arthritis or psoriasis suggests that use of certain disease-modifying anti-rheumatic drugs (DMARDs) lowers the risk of developing Type 2 diabetes, according to a study in the recent issue of JAMA.

Treatment of psoriasis and rheumatoid arthritis can include DMARDs such as tumour necrosis factor inhibitors (TNF), which are directed against the inflammatory response.

As background, the authors noted that prior research has indicated that rheumatoid arthritis (RA) and psoriasis predispose patients to insulin resistance. Treatment of psoriasis and rheumatoid arthritis can include DMARDs such as tumour necrosis factor inhibitors (TNF), which are directed against the inflammatory response. The relationship between these conditions and Type 2 diabetes suggests that systemic immunosuppression may also reduce the risk for developing Type 2 diabetes. Daniel H. Solomon, MD, MPH, of Brigham and Women's Hospital, Boston, and colleagues conducted a retrospective cohort study among 121,280 patients with a diagnosis of either RA or psoriasis on at least two visits. The analyses were conducted in the context of two large health insurance programmes, one in Canada and one in the United States, using administrative data. Average follow-up was 5.8 months and

began with the first prescription for a DMARD after the subject met study eligibility criteria. The investigators categorised drug treatments into four distinct groups: (1) TNF inhibitors with or without other DMARDs; (2) methotrexate without TNF inhibitors or hydroxychloroquine; (3) hydroxychloroquine without TNF inhibitors or methotrexate; or (4) other nonbiologic DMARDs without TNF inhibitors, methotrexate, or hydroxychloroquine. The researchers found 267 newly diagnosed cases of Type 2 diabetes: 55 cases among 3,993 treatment episodes with nonbiologic DMARD users; 80 cases among 4,623 treatment episodes with TNF inhibitor users; 82 cases among 8,195 treatment episodes with methotrexate users; and 50 cases among 5,682 treatment episodes with hydroxychloroquine users. The incidence rates for Type 2 diabetes were highest for individuals who switched to other nonbiologic DMARDs and lowest for TNF inhibitor users. "The fully adjusted models suggest a reduced relative risk of DM (diabetes mellitus/type 2 diabetes) for TNF inhibitor and hydroxychloroquine compared with other nonbiologic DMARDs," the authors reported. They concluded, "The findings from this epidemiologic study should be considered hypothesis-generating. However, considering these results in light of prior findings regarding improved insulin and glucose metabolism and reduced DM risk with hydroxychloroquine and TNF inhibitors, there is evidence suggesting a possible role for DMARDs and immunosuppression in DM prevention. A randomised controlled trial testing the ability of these agents to prevent DM among participants with systemic inflammatory disorders should be considered." In an accompanying editorial, Tim Bongartz, MD, MS, and Yogish Kudva, MD, of the Mayo Clinic College of Medicine, Rochester, Minnesota., wrote, "Prospective trials are needed to confirm the observational data and

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clarify which patients may benefit from these possible [multiple] effects of specific antiinflammatories. If hydroxychloroquine and antiTNF agents should truly enable two complex disease processes to be addressed with a single intervention, it will be crucial to investigate how much of their potential antidiabetic effects would add to good disease control, the durability of these effects, and the timing of treatment. Because even if treatment of chronic inflammatory disease can reduce the risk of diabetes, clinicians still will have to learn how to use specific anti-inflammatory agents to achieve optimal outcomes for both conditions."

Intranasal corticosteroid could help prevent obstructive sleep apnoea in children

SE OF A FLUTICASONE furoate nasal spray to treat paediatric obstructive sleep apnoea appears to reduce production of inflammatory cell proteins that contribute to the development of obstructive sleep apnea, researchers reported recently in Archives of Otolaryngology - Head & Neck Surgery.

"This reduction could contribute to the clinical efficacy of this class of medications in the treatment of childhood obstructive sleep apnoea syndrome.”

As background, the authors noted that obstructive sleep apnoea syndrome (OSAS) occurs in two percent to three percent of children. They added that prior research has suggested a role for inflammation in OSAS,

including increased release of certain cytokines and the presence of inflammatory cytokines. To determine the effect of intranasal corticosteroid therapy on inflammatory cytokines (non-antibody proteins secreted by cells that act as mediators between cells) in adenoid tissues in children with OSAS, Rania Esteitie, MD, and colleagues from The University of Chicago Medical Center and Pritzker School of Medicine, conducted a randomised, prospective exploratory study of 24 children ages 2 to 12 years who were undergoing adenotonsillectomy for OSAS that had been documented by polysomnography. They randomised the subjects into two groups, treatment (n=11) or no treatment (n=13). Children in the treatment group received 55µg (microgram) of fluticasone furoate nasal spray (an intranasal corticosteroid) once daily for two weeks. The 13 children in the notreatment group received no intranasal treatment. All children included in the analysis underwent adenotonsillectomy two weeks after initiation of treatment. The authors found that the treatment group had reduced levels of spontaneous IL-6 (a type I cytokine receptor that regulates cell growth and differentiation) production. IL-6 cytokine is secreted by T-regulatory cells and induces cell growth differentiation in certain cells. "In this study, we show reduction of IL-6, a proinflammatory cytokine, in adenoid tissue obtained from children with obstructive sleep apnoea syndrome treated with fluticasone furoate nasal spray," the authors wrote. "This reduction could contribute to the clinical efficacy of this class of medications in the treatment of childhood obstructive sleep apnoea syndrome."

Avastin and Lucentis shows similar efficacy for treating age-related macular degeneration (AMD)

ESULTS FROM THE first year of a twoyear clinical trial suggest that Avastin (bevacizumab) is as effective as Lucentis (ranibizumab injection) for the treatment of age-related macular degeneration (AMD). Lucentis is FDA-approved for treating AMD and Avastin is not. The interim findings from the Comparison of AMD Treatments Trials (CATT), was published online recently in the New England

Journal of Medicine. CATT is funded by the National Eye Institute (NEI), a part of the National Institutes of Health in Bethesda, Maryland. "Over 250,000 patients are treated each year for AMD, and a substantial number of them receive Avastin. Given the lack of efficacy data regarding Avastin for AMD treatment, the NEI had an obligation to patients and clinicians to conduct this study," said Paul A. Sieving, MD, PhD, director of the NEI.

PRN dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with PRN than with monthly treatment but overall visual results remained excellent.

Genentech, the maker of both drugs, originally developed Avastin to prevent blood vessel growth that enables cancerous tumors to develop and spread. In 2004, the FDA approved Avastin for the systemic treatment of metastatic colon cancer. Genentech later developed Lucentis, derived from a protein similar to Avastin, specifically for injection in the eye to block blood vessel growth in AMD. In 2005, two Genentech-sponsored clinical trials showed significant efficacy for Lucentis as a treatment of wet AMD. Between the announcement of these trial results and the approval and availability of Lucentis for AMD, ophthalmologists began injecting AMD patients with low doses of Avastin, due to its similarity to Lucentis. CATT was launched in 2008. In this interim analysis, the investigators reported results for 1,185 patients treated at 43 clinical centres in the United States. Investigators randomised subjects to one of four regimens for a year. They were treated with Lucentis monthly or PRN (“as needed” or pro re nata), or Avastin monthly or PRN. Enrollment criteria required that study participants had

active disease. Patients in the monthly dosing groups received an initial treatment and then an injection every 28 days. Patients in the PRN groups received an initial treatment and were examined every 28 days thereafter to determine need for additional treatment. PRN groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. Ophthalmologists involved in patient care were “blinded” to treatment use. Change in visual acuity served was the primary outcome measure for CATT. The investigators reported that, so far in the trial, visual acuity improvement was virtually identical (within one letter difference on an eye chart) for both drugs when given monthly. And no difference was found in the percentage of patients who had an important gain or loss in visual function. When the drugs were administered PRN, there also was no difference (within one letter) between drug efficacies. PRN dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with PRN than with monthly treatment but overall visual results remained excellent. "In addition to the primary finding of equivalence between Lucentis and Avastin for visual acuity, CATT also demonstrates that PRN dosing is a viable treatment option for either of these drugs," said Daniel F. Martin MD, study chair for CATT and chairman of the Cole Eye Institute at the Cleveland Clinic, Cleveland, Ohio. "Substantial visual acuity gains may be accomplished with a lower treatment burden." Investigators in the CATT study will continue to follow patients through a second year of treatment. These additional data will provide information on longer-term effects of the drugs on vision and safety. Sources: JAMA, Archives of Otolaryngology - Head & Neck Surgery, NIH/National Eye Institute

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View from the waiting room by Steve Devrell

This sporting life

AM A LIFELONG supporter of Bath Rugby. I can remember watching Bath play as a child in a near empty ‘Recreation Ground (‘The Rec’) where my father and I would stroll into the ground at five minutes to three and sit in the same seat every game. What was also invariable in those days of amateur rugby was the team sheet. The same old talented amateurs tuned out every week come rain or shine. It still seemed a pretty physical game, but compared to the ultra contact sport that the professional game has developed into it was a ‘walk in the park.’ These days you have to buy a ticket for £40, usually six weeks in advance, sit in a packed stadium and hold your breath over who might be fit for the game. It is almost unheard of for a player to play a whole season without injury. The vast majority spend anything from a month to a whole

These days you have to buy a ticket for £40, usually six weeks in advance, sit in a packed stadium and hold your breath over who might be fit for the game.

season on the injury list recovering from fairly major, but routine rugby injuries like broken eye sockets, torn biceps and broken hands. Footballers also suffer similar and expensive injuries that keep them sidelined for weeks on end. Who can forget the famous metatarsals of Messers Rooney and Beckham and how the nation went hysterical for their recoveries. The Sun even had us touching the X-Ray of David’s foot in some bizarre ritual of faith healing. The fact is that the pursuit of excellence in sport is causing many long-term and chronic injuries that may well have a permanent legacy in later life. But it is not only the professional sportsman who is at risk from injury. As we are told the benefits of exercise, the baby boomer generation of which I am a member have suddenly

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become obsessed with the desire to keep healthy and hopefully put a few more pages on our pension books. As a regular daytime gym member, I am surrounded by men of my age who seem to carry minor injuries as almost a badge of honour. A little limp here, a grimacing back stretch there seems to be recognition they are doing it right when in actual fact it proves they are doing things wrong. According to the Sports Injury Bulletin, published in the USA, the noncontact sports or activities like running, cycling, swimming or even stair walking do not sustain sudden catastrophic injuries like our sporting heroes in contact sports. Instead most keep fit type activities result in injuries from consistent overuse of the body. The American Journal on Sports Medicine also explodes some commonly held misconceptions and myths about exercise. Firstly, men are not more prone to injury than women, the figures are roughly equal. The light runner is not more likely to be injured than the heavier runner and the surface for running also has little effect on injuries. Another interesting experiment was carried out in Holland on 159 dedicated joggers. They were taught how to warm up, cool down and stretch effectively over a period of four months. Another group of 167 joggers were told just to start and finish their jog without ‘warming up or cooling down. Interestingly, the injury rate for both groups was identical, with approximately one injury per 200 hours of jogging. One study by the University of Hawaii found that athletes who stretch regularly before exercise were 33% more likely to suffer injury than those who do not. The same investigation however, determined that stretching carried out AFTER workouts did lower injury risks. One piece of advice that is consistent is the need to avoid exercise on too many consecutive days. The more consecutive days you exercise, the higher your chances of getting hurt. It is however beneficial to persevere with your exercise regimes as it has been proven that someone who is used to exercise and has built it into his regime over a period of time is far less likely to suffer injury than the novice. Gaining bodily strength is an important preventer of injury. This is particularly true in swimming where shoulder strength is the key factor in avoiding serious injury. When injury rates are expressed per hour of activity, the

risk of injury can be ranked by sport. Rates of five injuries per 1,000 hours are considered high. Rugby and Lacrosse produce the most mayhem with around 30 injuries per 1,000 hours. Squash has around 14 per 1,000 hours with aerobics also high with a rate of 11 injuries per 1,000 hours. Of the pursuits favoured by us baby boomers, using the gym’s rowing machine results in six injuries per 1,000 hours with the same result for treadmill walking or jogging. Tennis results in five injuries per 1,000 hours with outdoor cycling 3.5 per 1,000. Even unavoidable exercise like climbing stairs results in two injuries per 1,000 hours.

In general aerobic activities, including jogging the injuries have increased by 400%. In weight training it has increased by 200%. In golf it has increased by 300% and cycling injuries have increased by almost 70%.

It is the alarming increase in sporting injuries amongst people of my generation that is causing considerable concern. We are all urged to keep fit to stave off obesity and increase our chances of prolonging life, but this is achieved at a price. The almost obligatory desire for us baby boomers to join a gym or run the London marathon has its cost both in injuries and the medical care. A U.S. Consumer Safety Commission report has noted a 33% increase in hospital admissions for sports injuries amongst the baby boomer generation in the past seven years. The cost of this medical treatment in 2008 alone was over $20 billion. Fortunately deaths are still fairly infrequent, but the activity that has by far the largest fatalities is bicycle riding. Most of these involve other motor vehicles, but deteriorating eye sight and a failure to obey simple traffic regulations are important factors. Swimming is the next most dangerous sport for fatalities, with cramp being a significant cause of these incidents

coupled with an inflated perception of the victim’s swimming ability. Amongst the 45 – 64 year old population, there has been some reduction in sporting injuries in some key activities over the past ten years, tennis being a notable example. But in other activities there have been a dramatic increase in sports injuries for this age group. In general aerobic activities, including jogging the injuries have increased by 400%. In weight training it has increased by 200%. In golf it has increased by 300% and cycling injuries have increased by almost 70%. There are also concerns about the long-term affects of contact sports that involve repeated impact to the head. Soccer, rugby and boxing are prime examples of these. Reduced concentration, depression, paralysis, headaches and an increased risk of Alzheimer’s disease are all more likely for people who have participated in these sports when younger. There are undoubted benefits associated with maintaining fitness in later life, but what we baby boomers must appreciate in our forlorn quest for immortality is that pain is there for a reason. Although it might look good amongst our peers to have heavy strapping on our limbs or nurse a limp or manipulate a back twinge, these are not to be carried as a badge of honour; they are warning signs for potential longterm harm. There has never been a more misleading statement for my generation than No pain, No gain. Pain is our bodies warning system. Ignore it at your peril.

Steve Devrell is a retired deputy head teacher who contributes regularly for many local and national publications.

E V I D E N T I A • V O L U M E 5 • I S S U E 4 • AU G U S T / S E P T E M B E R 2 0 1 1

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Respect is earned With its superior BP reductions,1 reduced CV risk†2 and increased CHF survival rates3 compared to losartan, Amias has a heritage of evidence to be proud of. After all, no other ARB has been proven to both prolong life and reduce CHF hospitalisations in patients with heart failure irrespective of background therapy.4 This evidence, together with the unique breadth of its CHF licence,‡5 is why Amias continues to be the UK’s most prescribed ARB.

candesartan cilexetil For all the right reasons

Abbreviated Prescribing Information - Amias® (candesartan cilexetil) (Refer to Summary of Product Characteristics before prescribing) Presentation: Tablets containing 2mg, 4mg, 8mg, 16mg or 32mg candesartan cilexetil. Indication: Essential Hypertension in adults; Treatment of adult patients with heart failure and impaired left ventricular systolic function (LVEF ≤ 40%) as add-on therapy to ACE-inhibitors or when ACE-inhibitors are not tolerated. Dosage: In hypertension: Starting and usual maintenance dose is 8mg od with or without food. Most of the antihypertensive effect is attained within 4 weeks. In some patients, whose blood pressure is not adequately controlled, the dose may be increased to 16mg od and to a maximum of 32mg od. No dose adjustment is necessary in the elderly. A starting dose of 4mg is recommended for patients with renal impairment (including haemodialysis), with mild to moderate hepatic impairment and those at risk of hypotension due to intravascular volume depletion. In heart failure: Usual starting dose is 4mg od with or without food. Up-titration to the target dose of 32mg od or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks. No dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion, renal impairment or mild to moderate hepatic impairment. Amias can be administered with other heart failure treatment including ACE-inhibitors, beta-blockers, diuretics and digitalis or a combination of these. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and Amias is not recommended and should be considered only after careful evaluation of the potential benefits and risks. Safety and efficacy of Amias not established in children. Contraindications: Hypersensitivity to any component of Amias. Second and third trimesters of pregnancy. Severe hepatic impairment and/or

cholestasis. Warnings and Precautions: Monitoring of serum potassium and creatinine levels is recommended during dose titration of Amias in patients with heart failure and regularly in patients taking concomitant ACE-inhibitors and potassium sparing diuretics such as spironolactone. Periodic assessments of renal function is also recommended especially in elderly heart failure patients ≥ 75 years and in heart failure patients with impaired renal function. Hypotension may occur during treatment with Amias in heart failure patients. Risk of increased blood urea and serum creatinine in patients with renal artery stenosis. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment. Amias should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted. Possible hypotension during anaesthesia and surgery. Not recommended in patients with primary hyperaldosteronism. As with other vasodilators, use with caution in patients with aortic and/or mitral valve stenosis or obstructive hypertrophic cardiomyopathy. Amias should not be initiated during pregnancy. When pregnancy is confirmed, treatment with Amias should be stopped immediately, and, if appropriate, alternative therapy commenced. Amias is not recommended during breastfeeding. Drug Interactions: No clinically significant interactions identified with hydrochlorothiazide, warfarin, digoxin, oral contraceptives, glibenclamide, nifedipine and enalapril. Possible interaction with NSAIDs. Anti-hypertensive effect of Amias may be enhanced by other antihypertensives. Use with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Increase in serum potassium may occur with

potassium supplements and potassium sparing diuretics. Side-effects: In hypertension clinical trials, adverse events were mild and transient with the overall incidence similar to placebo. Overall incidence showed no association with dose or age. Adverse events commonly seen in clinical trials and postmarketing include: respiratory infection, dizziness/vertigo and headache. Adverse reactions seen very rarely include: Leukopenia, neutropenia, agranulocytosis, hyperkalaemia, hyponatraemia, nausea, increased liver enzymes, abnormal hepatic function or hepatitis, angioedema, rash, urticaria, pruritus, back pain, arthralgia, myalgia, renal impairment/failure, cough, decreased haemoglobin and increased creatinine and urea. In heart failure clinical trials (e.g. CHARM), the adverse event profile of Amias was consistent with the pharmacology of the drug and health status of the patients. In the CHARM clinical programme, 21% of the Amias group and 16.1% of the placebo group discontinued treatment due to adverse events. Adverse reactions commonly seen in clinical trials and postmarketing were: hyperkalaemia, hypotension and renal impairment/failure. Adverse reactions seen very rarely include leukopenia, neutropenia, agranulocytosis, hyponatraemia, dizziness, headache, cough, nausea, increased liver enzymes, abnormal hepatic function or hepatitis, angioedema, rash, urticaria, pruritis, back pain, arthralgia and myalgia. Legal Category: POM. Packs and Basic NHS Price: Blister packs. Amias 2mg, £3.58 for 7 tablets (PL 16189/0001); Amias 4mg, £3.88 for 7 tablets and £9.78 for 28 tablets (PL 16189/0002); Amias 8mg, £9.89 for 28 tablets (PL 16189/0003); Amias 16mg, £12.72 for 28 tablets (PL 16189/0004); Amias 32mg, £16.13 for 28 tablets (PL 16189/0007). PI Date Code: 04/2011 PI Approval Code: TA1104103 Marketing Authorisation Holder: Takeda UK Ltd., Takeda House, Mercury Park, Wycombe Lane,

Wooburn Green, High Wycombe, BUCKS HP10 0HH. For further information contact the Marketing Authorisation Holder: Telephone: 01628 537900, Fax: 01628 526615. ®Registered trademark owned by Takeda Pharmaceutical Company Ltd.

Please refer to the summary of product characteristics for details on the full side-effect profile and drug interactions of Amias. Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Takeda UK Ltd. References: 1. Meredith PA et al. J Hum Hypertens. 2010; 24(8): 525-31. 2. Kjeldsen SE et al. J Hum Hypertens 2010; 24(4): 263-273. 3. EklindCervenka M et al. JAMA 2011; 305(2): 175-82. 4. Young JB et al. Circulation 2004; 110: 2618-2626. 5. Takeda UK Ltd. Amias (candesartan cilexetil) Summary of Product Characteristics. www.medicines.org.uk. † Reduced risk of cardiovascular disease, morbidity, mortality and elective coronary revascularisation. ‡ Amias is the only ARB licensed for heart failure that can be prescribed as an alternative in patients intolerant to ACE-inhibitors, or in addition to an ACE-inhibitor with/without a betablocker in patients with LVEF ≤40%. Code: TA110579d Date of preparation: May 2011