Evidentia June/July 2011 issue by Peter Mas-Mollinedo

Volume 5 Issue 3 | June/July 2011 | ISSN 1753-464X

Researchers pinpoint brain region that influences gambling Statins â&#x20AC;&#x2DC;protect against kidney complications post elective surgeryâ&#x20AC;&#x2122; Low vitamin D levels in newborns linked to increase in respiratory disease Coffee may reduce risk of lethal prostate cancer

Conference reports from: London, New Orleans and Valencia

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

Bringing clinical evidence to practice in primary and secondary care

Contents 4

COVER STORY

Guest Editorial by Mr. Simon Bramhall How to address the gap between supply and demand for cadaveric organs

Volume 5 Issue 3 | June/July 2011 | ISSN 1753-464X

Low vitamin D levels in newborns linked to increased risk of respiratory infections

Researchers pinpoint brain region that influences gambling

Respiratory reports

Statins ‘protect against kidney complications post elective surgery’ Low vitamin D levels in newborns linked to increase in respiratory disease Coffee may reduce risk of lethal prostate cancer

Digital imaging software to create a ‘Google Earth' view of the bladder Urology reports

No pain, big gain

Conference reports from: London, New Orleans and Valencia

Pain study: Treatment of chronic low back pain can reverse abnormal brain activity and function

Researchers pinpoint brain region that influences gambling

Treating gout long-term with pegloticase is effective and safe

Angioplasty is non-inferior to CABG in some patients

To pump or not to pump?

Report from EULAR, London

Reporting from the ACC, New Orleans

Reports from Diabetes UK 2011, London

Strontium ranelate superior to bisphosphonates for bone formation in post-menopausal osteoporosis Meeting highlights from the ECCEO, Valencia

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 Mr. Simon Bramhall MD FRCS, consultant liver transplant surgeon, Queen Elizabeth Hospital, Birmingham

How to address the gap between supply and demand for cadaveric organs

HE NUMBER of organ donors in the UK is approximately 13 per million population (PMP) per year and has been gradually reducing for most of the last decade. Attempts have been made to improve rates of transplantation by using more marginal donors, splitting livers for two recipients and the increasing use of donation after cardiac death (DCD) donors. The numbers of living related donations has also been increasing ‘though this is largely confined to the recipients of kidneys. For

The falling rates of organ donation in the UK compared to rising rates elsewhere in Europe and North America led to the Department of Health establishing the Organ Donor Task Force.

the majority awaiting solid organ transplantation the number of donated organs remains the limiting factor in the number of transplants performed in the UK. The UK donation rate is now one of the lowest in the developed world while the US consistently achieves organ donation rates in excess of 25 PMP and Spain approximately 35 PMP. At the same time the need for solid organ transplantation is growing, with increases in the number of patients on the waiting lists of at least 8% per year. Evidence suggests that the UK population is supportive of organ donation, with 90% in favour during a UK

Contributors: Mr. Simon Bramhall, Maria Dalby, Steve Devrell, Gary Finnegan, Peter Mas-Mollinedo, Samuel Peters, Bruce Sylvester

survey carried out in 2003, and there are currently more than 17 million people signed up to the organ donor register. Concerns about the falling rates of organ donation in the UK compared to rising rates elsewhere in Europe and North America led to the Department of Health establishing the Organ Donor Task Force (ODTF) that reported in January 2008 and made a number of recommendations.1 These recommendations were constrained by the terms of reference which prevented recommendations that would require a change in the law. Attempts have been made to implement the recommendations and the implementation of some recommendations has been faster than others. Data from the Potential Donor Audit (carried out prospectively by NHS Blood and Transplant) suggests that there remains a large number of potential donors who are still not identified, brain stem death (BSD) tested or referred for consideration of donation and in addition anecdotal evidence from transplant surgeons suggests that there are a significant additional cohort of donors who are referred as DCD donors but who are likely to be either BSD at the time of referral or who could progress to BSD if managed with this end in mind. The Potential Donor Audit has been carried out since April 2004 and the original 36 month report2 suggested that the missed potential of BSD potential donors was in excess of 700 patients per year. The data collected at this time was however criticised as being based on a retrospective case note review and not based on reproducible clinical signs. Since then however, the data has been revised and the collection methods improved with significant input into these changes coming from the Intensive Care

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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community. The latest data is collected prospectively by embedded Specialist Nurses in Organ Donation (SNODs) and inclusion as a potential BSD donor now only includes those ventilated, in whom a diagnosis of catastrophic brain injury is confirmed, who have fixed dilated pupils and are apnoeic. Even with these more stringent criteria there are approximately 300350 missed potential per year. The greatest challenge in solid organ donation is how to address this missed potential.

Organ donor task force report 2008 The ODTF made 14 recommendations that were wide ranging in their remit.1 Many of these are easily measurable and have been implemented in full e.g. establishment of a nationwide organ donation organisation, expanding the number and centrally employing a donor transplant coordinator (now called SNODs) network, removal of financial disincentives, establishment of Clinical Leads for organ donation and Organ Donation

The greatest challenge in solid organ donation is how to address this missed potential.

Committees in each hospital and establishment of a National Organ Retrieval Service. There are others however that are less easy to measure and remain incompletely implemented e.g. promotion of donation to the BME population,

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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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personal and public recognition of donors, mandatory training, embracing organ donation as usual, resolution of legal, ethical and professional issues and formal guidelines for coroners. Perhaps the two most important recommendations that fall into this latter group are recommendations 5 and 7: • Minimum notification criteria for potential organ donors should be introduced on a UKwide basis. These criteria should be reviewed after 12 months in light of evidence of their effect, and the comparative impact of more detailed criteria should also be assessed • Brain stem death testing should be carried out in all patients where BSD is a likely diagnosis even if organ donation is an unlikely outcome There is no doubt that the ODTF recommendations have had an impact on rates of organ donation in the UK since their implementation and no doubt will continue to do so as their effect matures. The difficulty with implementing some of the recommendations e.g. 5 and 7 will however continue to impact on the gap between potential and actual numbers of organ donors. An additional and perhaps unforeseen consequence of the ODTF recommendations is the rapid increase in DCD donation at the expense of deceased after brain death (DBD) donation. This effect is difficult to measure but there is strong anecdotal evidence that decisions regarding futility and consequent treatment withdrawal are impacting on DBD donation. The ODTF concentrated primarily on DBD donation as this provides the core of solid organ transplantation. Treatment withdrawal however is such an inherent part of medical practice in the UK, along with restrictions on critical care beds and logistic changes that have recently occurred in patient management, that patients that are either BSD or would progress to BSD rapidly with appropriate clinical management are having treatment withdrawn on critical care units and being referred as DCD donors with the critical care team believing that they have done their ‘bit’ for organ donation.

presumed consent including Spain but very few use the system in practice. In Spain presumed consent had been part of statute for 10 years prior to the organisational changes without any

There are no ethical or legal barriers to introducing soft presumed consent legislation in the UK, however legal advice has suggested that a hard presumed consent law would be open to challenge under the European Convention on Human Rights.

effect on rates of donation.3 The US does not have presumed consent legislation. Both have impressive rates of organ donation and both have seen a rapid increase in a relatively short period of time. Sweden switched to a presumed consent system in 1996 but continues to have very poor rates of organ donation (10 PMP) and attempts to introduce presumed consent legislation in Brazil and France led to a backlash against organ donation. The consent rates in the UK are poor when compared to other European countries (approximately 60% compared to over 80% in Spain) however UK consent rates are actually very similar to those in the US but donation rates in the UK are half that of the US. This implies that there are factors other than consent rates that

need addressing in the UK prior to blaming our low rates of organ donation on family consent.2 There are no ethical or legal barriers to introducing soft presumed consent legislation in the UK, however legal advice has suggested that a hard presumed consent law would be open to challenge under the European Convention on Human Rights. There is a belief amongst some members of the medical profession that the introduction of presumed consent might damage the relationship of trust between clinicians caring for patients at the end of life and their families.4 There is a possibility that some clinicians could opt out of donation programmes at a time when their support is required to improve rates of

The introduction of a system of presumed consent would be highly complex and costly if it were to command the trust of the involved professions and the general public.

organ donation. In addition evidence from recipients of organs suggests that many need to know that organs had been donated without coercion by the organ donor and their family and the family’s of organ donors who usually find great comfort in being an active part of the decision to donate. CONTINUED ON PAGE 6 >

Presumed consent Presumed consent is alternatively known as an ‘opt out’ system and means that unless the deceased has expressed a wish in life NOT to be an organ donor then consent will be assumed. This can be divided into what is known as a ‘hard opt out’ where the family are not consulted or a ‘soft opt out’ when the family’s wishes are considered in the same manner as with the current ‘opt in’ system. A number of countries have a system of E V I D E N T I A • V O L U M E 5 • I S S U E 3 • J U N E / J U LY 2 0 1 1

Guest editorial by Mr. Simon Bramhall MD FRCS, consultant liver transplant surgeon, Queen Elizabeth Hospital, Birmingham < CONTINUED FROM PAGE 5

The introduction of a system of presumed consent would be highly complex and costly if it were to command the trust of the involved professions and the general public. Every member of the UK public at the time of introduction and moving forward would need to be contacted and offered the option of ‘opting out’. This would require a significant and sustained communication programme and any ‘opt out’ register would need a robust IT system to support the process. There are real concerns amongst the general public about centrally controlled IT registers containing personal information and introduction of such a personal database at this time is probably ill conceived.5

Required referral based on clinical triggers The US recognised that they had a problem with rates or organ donation in the late 1990s and decided to address this by legislative change.6 They already had a well established and appropriately funded Organ Procurement Organisation (OPO and in 1998 introduced changes to the law to support their organisation. All acute care hospitals had to have policies in place that defined imminent death and required timely notification about all patients who meet the definition. Hospitals & OPOs quickly moved to implement the regulations by defining imminent death, revising referral systems, and holding each other accountable for adhering to the standards. The guidelines suggested: A patient with severe, acute brain injury who requires mechanical ventilation, is in an ICU or

emergency department, and has clinical findings consistent with a score on the GCS that is less than or equal to a mutually agreed upon threshold; or is being evaluated for a diagnosis of brain death; or has had withdrawal of lifesustaining therapies ordered by a physician. In addition, many incorporated the absence of certain brain stem reflexes (i.e., pupillary light response, corneal reflex, caloric response, gag reflex, cough reflex and respiratory effort) into their definition of imminent death. These changes allowed the establishment of a denominator against which to monitor identification, BSD testing and referral of all potential donors. US hospitals were already receiving financial recompense for the organ retrieval operation and in addition were now penalised for failure to identify, test and refer. These legislative changes led to a rapid increase in donor numbers and numbers of organs retrieved from each donor. This in turn led to dramatic improvements in the number of transplants performed and waiting time for transplantation. An additional perhaps unforeseen benefit was a reduction in the number of living related transplants performed with consequent benefits to those potential living donors and the US economy.

Conclusion The ODTF recommendations implemented as they currently stand have undoubtedly had an impact on rates of organ donation in the UK. The failure to fully implement all 14 recommendations because of understandable difficulties will mean that alone they are unlikely to realise the 50%

increase in organ donation that was promised. Many influential individuals and organisations have expressed a desire to move forward with legislative change for presumed consent. It is possible, if introduced carefully that this could have an impact on family consent rates but equally could backfire as it has done in other countries. In addition it seems a little unfair to place the blame for poor rates of organ donation on families when the data suggests that the medical profession is far from perfect with a large number of missed potential. If after addressing our own house there was still concern about rates of donation then presumed consent legislation could be considered. There is no doubt that legislation introducing required referral based on clinical triggers works, we just have to look to the US to see that and it undoubtedly works on a number of levels but not least because it allows identification of the real denominator with no room for excuses, against which individuals, critical care units and hospitals can be measured. References: 1. Organ Donation Taskforce. Organs for Transplants: A report from the Organ Donation Taskforce 2008. See:http://www.dh.gov.uk/en/Publicationsandstatistics/P ublications/PublicationsPolicyAndGuidance/DH_082122. 2. Barber K, Falvey S, Hamilton C, Collett D, Rudge C. Potential for organ donation in the United Kingdom: audit of intensive care records. British Medical Journal 2006;332:1124-1127. 3. British Medical Journal 2008;337:a1614. 4. Survey, Intensive Care Society members, 2008. 5. Anderson R, Brown I, Dowty T, Inglesant P, Heath W, Sasse A. Database state. A report commissioned by the Joseph Rowntree Trust Foundation. 2009. 6. 63 Federal Register 33856 (1998) (codified at 42 CFR 482).

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Respiratory reports by Bruce Sylvester

Low vitamin D levels in newborns linked to increased risk of respiratory infections

ESEARCHERS REPORT that levels of vitamin D in newborn babies could predict risk of respiratory infections in infancy and wheezing in early childhood, but not the risk of developing asthma. The study was published in a recent issue of Pediatrics. "Our data suggest that the association between vitamin D and wheezing, which can be a symptom of many respiratory diseases and not just asthma, is largely due to respiratory infections," said lead investigator Carlos Camargo, MD, DrPH, of the Massachusetts General Hospital in Boston, Massachusetts. "Acute respiratory infections are a major health problem in children. For example, bronchiolitis – a viral illness that affects small airway passages in the lungs – is the leading cause of hospitalisation in U.S. infants," he added. As background the investigators noted that prior research by Camargo's team suggested that children of women who took vitamin D supplements during pregnancy were less likely to develop wheezing during childhood. They designed the newly reported study to evaluate the relationship between the blood levels of vitamin D in newborns and the ensuing risk of respiratory infection, wheezing and asthma. The researchers analysed data from the New Zealand Asthma and Allergy Cohort Study,

which included over 1,000 children in the cities of Wellington and Christchurch. Midwives or study nurses gathered samples of umbilical cord blood from newborns. The investigators analysed the cord blood samples for levels of 25-hydroxyvitamin D (25OHD), the best measure of vitamin D status. Subsequently, the mothers answered questionnaires, which included questions about respiratory and other infectious diseases, the incidence of wheezing and any diagnosis of asthma. The questionnaires were completed at months three and 15 postpartum and then annually until the children were five years old. Cord blood samples from 922 newborns were available. According to the investigators, the target level for 25OHD should be as high as 100nmol/L. More than 20% of the infants showed 25OHD levels of less than 25nmol/L. The average level for the whole group was 44nmol/L. They noted that lower levels were associated with children born in winter, children of lower

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socioeconomic status and children with familial histories of asthma and smoking. The investigators reported that at age three months, infants with 25OHD levels below 25nmol/L were twice as like to have developed respiratory infections as those with levels of 75nmol/L or higher. Results from years 0-5 showed an association between lower neonatal 25OHD level and a higher risk of wheezing. The researchers found no significant association between 25OHD levels and diagnosis of asthma by age five years. Camargo added, "There's a likely difference here between what causes asthma and what causes existing asthma to get worse. Since respiratory infections are the most common cause of asthma exacerbations, vitamin D supplements may help to prevent those events, particularly during the fall and winter when vitamin D levels decline and exacerbations are more common. That idea needs to be tested in a randomised clinical trial, which we hope to do next year." Source: Massachusetts General Hospital

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Respiratory reports by Bruce Sylvester

Simple blood test detects early emphysema in smokers before symptoms appear

URING A REGULAR annual physical exam, blood is usually drawn to check the health of a person's heart, kidneys and liver. Now, researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center say a blood test that detects the early development of emphysema - well before symptoms occur may someday also be offered. In the recent online edition of the American Journal of Respiratory and Critical Care Medicine, the researchers say that because most cases of emphysema are caused by smoking, the test they are developing can warn smokers about impending development of the untreatable disease - which is currently a major cause of disability and death in the U.S. Not all smokers develop emphysema, but those who find out they are at risk will be motivated to quit to halt progression of the disease, says the study's lead investigator, Dr. Ronald G. Crystal, chairman and Professor of Genetic Medicine and the Bruce Webster Professor of Internal Medicine at Weill Cornell Medical College and chief of the Division of Pulmonary and Critical Care Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "We know, from other studies, that smokers who learn from objective evidence that their health is in danger are much more likely to quit," he says. "That is the only thing that will help them avoid this deadly disorder." Emphysema and chronic bronchitis are the twin disorders that make up chronic obstructive pulmonary disease (COPD), which is now the fourth leading cause of death in the U.S. Given the aging population, COPD is soon expected to move up to third in mortality prevalence, Dr. Crystal says. The new test measures particles that are shed by capillaries that surround the alveoli in lungs. These particles are debris shed by ongoing injury to the air sacs - damage that eventually results in devastation of the sacs and the "Swiss cheese" appearance of the lungs. As the sacs are destroyed, shortness of

breath develops because of lack of oxygen to the body which eventually leads to inability to remove carbon dioxide from the blood. Dr. Crystal and his colleagues reasoned that as capillaries surrounding the air sacs are being injured, the debris would be carried out by the blood supply and could potentially be quantified as a disease biomarker. So they

"What we are looking for are elevated levels of EMPs. For smokers, this is the equivalent of a smoke detector sounding its alarm; elevated levels of EMPs suggest their air sacs are being injured and it is time to act." began to look for evidence of what they called endothelial microparticles (EMP). "Our blood vessels are always being replenished, so we all have some level of EMPs in our blood," he says. "What we are looking for are elevated levels of EMPs. For smokers, this is the equivalent of a smoke detector sounding its alarm; elevated levels of EMPs suggest their air sacs are being injured and it is time to act." To do this, the researchers enrolled three groups of people - healthy nonsmokers, healthy smokers, and smokers with early evidence of lung destruction. Study participants had their medical histories taken, and to gauge lung function in these participants, all underwent two pulmonary function tests. One is spirometry, which measures the volume and speed of air as it is inhaled and exhaled from the lungs. The other, known as DLCO, is the only lung function test available today that can detect emphysema in patients. It uses a machine that measures the ability of gases to diffuse across the alveolar-

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capillary membrane. The researchers found a 95% positive correlation between elevated EMPs in the blood and an abnormal DLCO test result, meaning that it detected nearly all verified cases of early emphysema in participants. Two other independent groups of participants were then given the same group of tests - spirometry, DLCO and the EMP blood test - and, once again, a positive EMP finding correlated with an abnormal DLCO 95% of the time. Differences in the spirometry findings had no bearing on results of DLCO or EMP. DLCO, which must be administered by a pulmonologist, is most often used to confirm a suspicion of emphysema, Dr. Crystal says. By contrast, the EMP blood test is designed to be a simple, low-cost screening tool that can pick up development of emphysema in individuals who show no signs of the disorder. "We need a blood test that can be administered to the 20% of American adults who smoke as well as nonsmokers exposed to secondhand smoke - all who may not understand their risk of developing this progressive lung disease," says Dr. Crystal. The researchers are conducting further studies of the EMP test in larger groups of participants in order to validate these initial findings. The study was funded by grants from the National Institutes of Health. Co-authors include Drs. Cynthia Gordon, Kirana Gudi, Anja Krause, Rachel Sackrowitz, Ben-Gary Harvey and Yael Strulovici-Barel, all from NewYork-Presbyterian/Weill Cornell and Dr. Jason Mezey from Cornell University, Ithaca, N.Y. For more information, patients may call (866) NYP-NEWS.

Anticholinergic drug treatment of men with COPD related to increased risk of urinary retention

SE OF INHALED anticholinergic drugs to treat men with chronic obstructive pulmonary disease (COPD) is linked to an increased risk of developing acute urinary retention, an inability to urinate which is considered a medical emergency.

COPD affects about 10% of people age 40 years and older. Inhaled anticholinergic medications relax airway muscles, reducing obstructions to airflow.

Researchers reported this finding in a recent issue of Archives of Internal Medicine, a JAMA publication. In a commentary accompanying the article, Sonal Singh, M.D., from The Johns Hopkins University in Baltimore and Curt D. Furberg, M.D., Ph.D., from Wake Forest University, Winston-Salem, N.C., said that inhaled anticholinergic drugs do not completely stall the progress of COPD or extend life. "Therefore, information on serious adverse effects associated with IACs [inhaled anticholinergic drugs ] can potentially alter their benefit-harm assessment." As background, the authors noted that COPD affects about 10% of people age 40 years and older. Inhaled anticholinergic medications relax airway muscles, reducing obstructions to airflow. But, the authors added that, "there is uncertainty about whether IACs cause clinically important systemic anticholinergic effects." Anne Stephenson, M.D., Ph.D., from St.

Michael's Hospital, Toronto, Canada, led a retrospective study analysing data from the Ontario Universal Health Insurance Program. She and her colleagues identified data on individuals aged 66 years or older with COPD, and they searched the data for treatment with inhaled anticholinergic drugs and development of acute urinary retention, between April 2003 and March 2009. Also, they grouped the data by various inhaled anticholinergic drug regimens. Among the original cohort of 565,073 patients with COPD, a total of 9,432 men and 1,806 women developed acute urinary retention. The relationship was not statistically significant in women, but it was significant in men. Among inhaled anticholinergic drugs users, the risk of developing acute urinary retention was about 40% higher in men who had been using inhaled anticholinergic drugs for one month or less and about 80% higher in men with an enlarged prostate gland. Simultaneous use of both short-acting and longacting inhaled anticholinergic drugs significantly increased the odds of developing acute urinary retention . "Physicians should highlight for patients the possible connection between urinary symptoms and inhaled respiratory medication use to ensure that

changes in urinary flow (ie, incomplete voiding, urinary incontinence, and decreased urinary flow) are reported to the physician prescribing the IAC," said the authors. They added that the risk of developing acute urinary retention might be reduced by taking the lowest effective dose of inhaled anticholinergic drugs and avoiding combinations that increase risk. "Physicians and the public need to be aware of the potential for this significant adverse event," the authors concluded, "so that preventive measures and potential therapy can be considered." Source: JAMA/Archives of Internal medicine

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Urology reports

Digital imaging software to create a ‘Google Earth' view of the bladder

“This is trying to bring endoscopy to a more digital, modern age.” Professor Eric Seibel

Researchers at the University of Washington are proposing a more automated approach that could be cheaper, more comfortable and

Figure one The UW scope looks and feels like a piece of angel-hair pasta. In this illustration, the green ball represents the bladder. The UW scope follows a spiraling path, shown with arrows, to image the whole interior. The UW software checks that the scope's path has covered the entire surface of the bladder.

more convenient for both doctors and patients. Their system would use the UW's ultrathin laser endoscope, which is like a thin piece of cooked spaghetti, in combination with software that stitches together images from the scope's path to create a full, 3-D panorama of the bladder interior. The semi-automated scan could be done by a nurse or technician. Resulting images could be reviewed by a urologist at a later time, potentially in another city or country. "This is trying to bring endoscopy to a more digital, modern age," said co-author Eric Seibel, a UW research associate professor of mechanical engineering. "In the current model a very highly trained person has to do all the manual controls. There's no electronic record, no longitudinal studies, no remote diagnosis and you can't send records anywhere." See figure one.

doctors. Often no records exist beyond the doctor's notes. The UW software checks that no part of the organ was missed, so a nurse or technician could administer the procedure – especially using a small scope that doesn't require anaesthesia. See figure two.

LADDER CANCER IS the fourthmost-common cancer in men and one of the most expensive cancers to treat from diagnosis to death. After initial diagnosis and surgery, patients must return to the urologist at least yearly for a costly, timeconsuming and uncomfortable bladder scan. Tumours recur in more than half of patients.

Figure two The research has been presented recently in Washington, D.C., at the annual meeting of the American Urological Association. Currently, urologists conduct bladder exams using an endoscope that's manipulated around the bladder during the roughly five minute scan.

"There's a potential with this technology to semi-automate or fully automate the examination." Dr. Michael Porter

Because a specialist is required, some patients have to travel long distances for appointments. Unlike ultrasounds, X-rays and CT scans, endoscopies are only performed by medical

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A 3-D digital reconstruction of the inside of a stained pig's bladder. The images were taken using the UW’s ultrathin, flexible endoscope, and stitched together into a mosaic using UW software. A urologist would inspect this 3-D image looking for signs of tumour growth. "There's a potential with this technology to semi-automate or fully automate the examination," said Dr. Michael Porter, a UW assistant professor of urology. "It's a few years down the road, at least, but the potential is there." The current user interface projects the reconstructed organ onto a spherical ball or onto a flat map. The resulting mosaic matches the images to a single pixel of accuracy. Ultimately, the digital display would incorporate all the original frames, so a doctor could zoom in on an area of interest and observe from all angles at the highest resolution. "Essentially, I want to give urologists a

Google Earth view of the bladder," said coauthor Timothy Soper, a UW research scientist in mechanical engineering. "As you move the mouse over the 3-D surface it would show the individual frame showing exactly where that image came from. So you could have the forest and the trees." Reviewing the resulting panoramic image would likely require less of the urologist's time

The UW software could be used with any endoscope, though the team sees particular benefit in combining it with its flexible endoscope.

than performing a manual inspection. At the meeting, Porter will present the software and the user interface, as well as preliminary results of 3-D panoramas from a commercially available endoscope inserted into a painted glass bulb, a stained pig bladder and a normal human bladder. The UW software could be used with any endoscope, though the team sees particular benefit in combining it with its flexible endoscope. The UW scope is just 1.5 mm wide, about half the size of its smallest competitor (most bladder scopes are as thick as a pencil, while the UW's is like a strand of angel hair pasta with a tip the size of a grain of rice). It captures finer-grained images than existing flexible endoscopes. The tiny size is possible because of a novel design that swings a single optical fibre back and forth to scan a colour

image pixel by pixel. The tip of the UW device will contain a steering mechanism that directs the movement of the scope during the internal exam. Another advantage of using the UW scope in urology is that it can detect newly approved diagnostic cancer-cell markers that are best seen using low-power lasers, which are already used in the UW device. Until recently a Japanese company held exclusive rights to develop medical applications for the UW scope. That license expired last month, and UW researchers are now exploring their tool's use for urology. They are waiting for

U.S. Food and Drug Administration safety clearance to test the scope for human bladder scans and pursuing funding options. The next step will ask urologists to compare their experience of performing a diagnosis from a live video scan of a human bladder with the 3-D digital recreation. The research was funded by a grant from the Wallace H. Coulter Foundation in the UW's Department of Bioengineering, and by the UW's Center for Commercialization For further information contact: Hannah Hickey hickeyh@uw.edu

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Urology reports

Coffee may reduce risk of lethal prostate cancer

EN WHO REGULARLY drink coffee appear to have a lower risk of developing a lethal form of prostate cancer, according to a new study led by Harvard School of Public Health (HSPH) researchers. What's more, the lower risk was evident among men who drank either regular or decaffeinated coffee.

“Our study is the largest to date to examine whether coffee could lower the risk of lethal prostate cancer." Professor Lorelei Mucci

The study will be published in an online edition of the Journal of the National Cancer Institute. "Few studies have specifically studied the association of coffee intake and the risk of lethal prostate cancer, the form of the disease that is the most critical to prevent. Our study is the largest to date to examine whether coffee could lower the risk of lethal prostate cancer," said senior author Lorelei Mucci, associate professor of epidemiology at HSPH. Lethal prostate cancer is cancer that causes death or spreads to the bones. Prostate cancer is the most frequently diagnosed form of cancer and the second leading cause of cancer death among U.S. men, affecting one in six men during their lifetime. More than two million men in the U.S. and 16 million men worldwide are prostate cancer survivors. "At present we lack an understanding of risk factors that can be changed or controlled to lower the risk of lethal prostate cancer. If our

findings are validated, coffee could represent one modifiable factor that may lower the risk of developing the most harmful form of prostate cancer," said lead author Kathryn Wilson, a research fellow in epidemiology at HSPH. The researchers chose to study coffee because it contains many beneficial compounds that act as antioxidants, reduce inflammation, and regulate insulin, all of which may influence prostate cancer. Coffee has been associated in prior studies with a lower risk of Parkinson's disease, Type 2 diabetes, gallstone disease, and liver cancer or cirrhosis. The study examined the association between coffee consumption and the risk of prostate cancer, particularly the risk for aggressive prostate cancer among 47,911 U.S. men in the Health Professionals Follow-Up Study who reported their coffee consumption every four years from 1986 to 2008. During the study period, 5,035 cases of prostate cancer were reported, including 642 fatal or metastatic cases. Among the findings: • Men who consumed the most coffee (six or more cups daily) had nearly a 20% lower risk of developing any form of prostate cancer.

• The inverse association with coffee was even stronger for aggressive prostate cancer. Men who drank the most coffee had a 60% lower risk of developing lethal prostate cancer. • The reduction in risk was seen whether the men drank decaffeinated or regular coffee, and does not appear to be due to caffeine. • Even drinking one to three cups of coffee per day was associated with a 30% lower risk of lethal prostate cancer. • Coffee drinkers were more likely to smoke and less likely to exercise, behaviours that may increase advanced prostate cancer risk. These and other lifestyle factors were controlled for in the study and coffee still was associated with a lower risk. The results from this study need to be validated in additional populations that have a range of coffee exposure and a large number of lethal prostate cancer cases. If confirmed, the data would add to the list of other potential health benefits of coffee. The authors currently are planning additional studies to understand specific mechanisms by which coffee may specifically lower the risk of lethal prostate cancer.

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Pain study

No pain, big gain Treatment of chronic low back pain can reverse abnormal brain activity and function

T LIKELY COMES as no surprise that low back pain is the most common form of chronic pain among adults. Lesser known is the fact that those with chronic pain also experience cognitive impairments and reduced grey matter in parts of the brain associated with pain processing and the emotional components of pain, like depression and anxiety. In a longitudinal study published recently in the Journal of Neuroscience, a group of pain researchers from McGill University and the McGill University Health Centre (MUHC) posed a fundamental question: If you can alleviate chronic low back pain, can you reverse these changes in the brain? The answer is, Yes. The team began by recruiting, through the Orthopedic Spine Clinic and the Alan Edwards Pain Management Unit at the MUHC, patients who have had low back pain for more than six months and who planned on undergoing treatment – either spinal injections or spinal surgery – to alleviate their pain. MRI scans were conducted on each subject before and six months after their procedures. The scans measured the cortical thickness of the brain and brain activity when the subjects where asked to perform a simple cognitive task. "When they came back in, we wanted to

know whether their pain had lessened and whether their daily lives had improved," said the study's senior author, Laura S. Stone from McGill's Alan Edwards Centre for Research on Pain. "We wanted to see if any of the pain-

The scans measured the cortical thickness of the brain and brain activity when the subjects where asked to perform a simple cognitive task.

related abnormalities found initially in the brain had at least slowed down or been partially reversed." Not only did the team observe recovery in the anatomical function of the brain, but also in its ability to function. After the subjects were treated, researchers found increased cortical thickness in specific areas of the brain that were related to both pain reduction and

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physical disability. And the abnormal brain activity observed initially during an attentiondemanding cognitive task was found to have normalised after treatment. While more research would be needed to confirm whether chronic pain actually causes these changes in the brain, Stone hypothesises that chronic low back pain, at the very least, maintains these differences. "If you can make the pain go away with effective treatment," she added, "you can reverse these abnormal changes in the brain." Other contributing researchers on this study include David A. Seminowicz (formerly of McGill, currently at the University of Maryland); Timothy H. Wideman (McGill); Lina Naso (McGill); Zeinab Hatami-Khoroushahi (McGill); Summaya Fallatah (McGill); Mark A. Ware (McGill/MUHC); Peter Jarzem (McGill/MUHC); M. Catherine Bushnell (McGill); Yoram Shir (McGill/MUHC); and Jean A. Ouellet (McGill/MUHC).

INTRODUCING A NEW CLASS IN PAIN RELIEF1

Start to unlock severe chronic back pain with Palexia SR

Palexia SR (tapentadol prolonged release tablets) is indicated for the treatment of severe chronic pain in adults, which can be adequately managed only with opioid analgesics2 Tapentadol is a Controlled Drug, Schedule 2

Visit evi.palexia.co.uk for more information

PALEXIA® and PALEXIA SR® Prescribing Information Refer to the Summary of Product Characteristics (SmPCs) before prescribing. Presentation: Palexia: 50 mg (white) and 75 mg (pale yellow) film-coated tablets contain 50 mg and 75 mg of tapentadol (as hydrochloride) respectively. Palexia SR: 50 mg (white), 100 mg (pale yellow), 150 mg (pale pink), 200 mg (pale orange) and 250 mg (brownish red) prolonged-release tablets contain 50 mg, 100 mg, 150 mg, 200 mg and 250 mg of tapentadol (as hydrochloride) respectively. Indication: Palexia is indicated for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics. Palexia SR is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. Dosage and method of administration: Individualise according to severity of pain, the previous treatment experience and the ability to monitor the patient. Swallowed whole with sufficient liquid, with or without food. Palexia SR should not be divided or chewed. Palexia dosage: Initial dose 50 mg every 4 to 6 hours. On the first day of dosing, an additional dose may be taken 1 hour after the initial dose, if no pain control. The first day’s dose should not exceed 700 mg. Maximum maintenance daily dose of up to 600 mg. Palexia SR dosage: Initial dose 50 mg twice a day. Switching from other opioids may require higher initial doses. Titrate in increments of 50 mg twice a day every 3 days for adequate pain control. Total daily doses greater than 500 mg not recommended. Discontinuation of treatment: Taper dose gradually to prevent withdrawal symptoms. Renal/hepatic impairment: Not recommended in severe patients. Caution and dose adjustments with moderate hepatic impairment.

Elderly: May need dose adjustments. Children below 18 years: Not recommended. Contraindications: Hypersensitivity to ingredients, suspected or having paralytic ileus, acute alcohol intoxication, hypnotics, centrally acting analgesics or psychotropics. Not for use when mu-opioid receptor agonists are contraindicated (e.g. significant respiratory depression, acute or severe bronchial asthma or hypercapnia). Special warnings and precautions: At risk patients may require monitoring due to misuse, abuse, addiction or diversion. At high doses or in mu-opioid receptor agonist sensitive patients, dose-related respiratory depression may occur. Caution and monitoring required with impaired respiratory function. Should not use in patients susceptible to intracranial effects of carbon dioxide retention (e.g. increased intracranial pressure, impaired consciousness or coma). Use with caution with head injury, brain tumors, history or at risk of seizures, moderate hepatic impairment, biliary tract disease or acute pancreatitis. Not recommended with severe renal or hepatic impairment. Avoid use in patients who have taken monoaminie oxidase inhibitors (MAOIs) within the last 14 days, due to cardiovascular events. Should not use with hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Interactions: Use with benzodiazepines, barbiturates and opioid analgesics, antitussive drugs and substitutive treatments may enhance the risk of respiratory depression. Central nervous system (CNS) depressants (e.g. benzodiazepines, antipsychotics, H1-antihistamines, opioids, alcohol) can enhance the sedative effect and impair vigilance. Consider dose reduction with respiratory or CNS depressant agents. In isolated cases, serotonin syndrome has been reported with Palexia/Palexia SR in

combination with serotoninergic medicinal products (e.g. serotonin reuptake inhibitors). Care should be taken with mixed mu-opioid agonist/ antagonists or partial mu-opioid agonists due to risk of reducing the analgesic effect. Use with strong inhibitors of uridine diphosphate transferase isoenzymes (involved in glucuronidation) may increase systemic exposure of Palexia/Palexia SR. Risk of decreased efficacy or adverse events if used with strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John’s Wort). Pregnancy and lactation: Do not use. Driving and using machines: May have major effect on ability to drive and use machines, especially at the beginning or change in treatment, in connection with alcohol or tranquilisers. Undesirable effects: Very common (≥1/10): dizziness, somnolence, headache, nausea. Palexia only: vomiting. Palexia SR only: constipation. Common (≥1/100, <1/10): decreased appetite, anxiety, sleep disorder, tremor, flushing, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change. Palexia only: confusional state, hallucinations, dry mouth, muscle spasms, constipation, abnormal dreams. Palexia SR only: depressed mood, nervousness, restlessness, disturbance in attention, involuntary muscle contractions, dyspnoea, vomiting, mucosal dryness, oedema. Other important undesirable effects: Palexia only: respiratory depression (uncommon ≥1/1000, <1/100), hypersensitivity (rare ≥1/10,000, <1/1000); Palexia SR only: drug hypersensitivity (uncommon ≥1/1000, <1/100), respiratory depression (rare ≥1/10,000, <1/1000). No evidence of increased risk of suicidal ideation or suicide with Palexia/Palexia SR. Consult the SmPCs for full details. Overdose: Seek specialist treatment (see SmPCs). Legal classification: POM, CD (Schedule

II). Marketing Authorisation numbers, pack sizes and basic NHS cost: Palexia: 50 mg: PL 21727/0032, 28 (£12.46) and 56 pack (£24.91); 75 mg: PL 21727/0033, 28 (£18.68) and 56 pack (£37.37). Palexia SR: 50 mg: PL 21727/0041, 28 pack (£12.46) and 56 pack (£24.91); 100 mg: PL 21727/0042, 56 pack (£49.82); 150 mg: PL 21727/0043, 56 pack (£74.73); 200 mg: PL 21727/0044, 56 pack (£99.64) and 250 mg: PL 21727/0045, 56 pack (£124.55). Marketing Authorisation Holder: Grünenthal Ltd, Regus Lakeside House, 1 Furzeground Way, Stockley Park East, Uxbridge, Middlesex, UB11 1BD, UK. Date of preparation: March 2011. P10 0057b

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Grünenthal Ltd (telephone 0870 351 8960). References 1. Kress HG. Eur J Pain. 2010; 14(8):781–783 2. Palexia SR, Summary of Product Characteristics. 06 August 2010 P11 0078e Date of preparation: February 2011.

European Congress of Rheumatology/European League Against Rheumatism Report from EULAR, London by Bruce Sylvester

From EULAR, the annual congress of the European Congress of Rheumatology/European League Against Rheumatism, we report on three highly clinically significant studies. EULAR took place in London in May and was attended by over 7,000 people.

Treating gout long-term with pegloticase is effective and safe

NVESTIGATORS FROM AN extension study of a 24-week Phase III trial report that gout patients who respond well to pegloticase (Krystexxa, Savient) have achieved long-term improvement of symptoms, and the drug is safe for up to 2.5 years. The study was an open-label extension of a randomised, controlled, Phase III 24-week trial of pegloticase. The extension lasted 126 weeks. The goal of the extension was to determine the risks and benefits of long-term use of pegloticase, with a focus on outcomes in patients treated every two weeks, the recommended regimen. “The findings are fantastic,” said commentator Maxime Dougados, MD, EULAR President and Professor of Rheumatology at René Descartes University in Paris, France, at a press briefing preceding the presentation of the study in a general session. He sugested the data

would contribute significantly to a reexamination of regulatory guidelines in Europe for gout treatment. In the prior 24-week study, researchers enrolled 212 gout patients who were refractory to conventional therapy. Of these, 84 received 8mg pegloticase every four weeks, 85 (mean age of 56.3 years, mean disease duration of 15.4 years, 80% male) received 8mg pegloticase every two weeks, and 43 received placebo. The researchers in the 24-week trial found that pegloticase 8mg every two weeks normalised serum uric acid within 24 hours, and that 42% (36/85) of subjects treated every two weeks became “persistent responders,” with uric acid < 6mg/dL at 6 months. These persistent responders also achieved significant reductions of gout flares at 24 weeks. They had a mean of 6.6 painful flares/year at baseline, and most achieved no- flare status by the end of 24 weeks. Subjects who completed the 24-week trial entered the multi-year and open-label extension. Among the 35 persistent responders entering the open-label extension, 19 chose to receive pegloticase therapy 8mg every two weeks. The investigators reported that 84% of these subjects continued to have normalised uric acid for greater than two years. Among subjects who chose pegloticase 8mg every two weeks in the extension study, most were flare-free by its end. Of the 58 subjects who, at baseline in the 24week trial and in the extension trial, received pegloticase 8mg every two weeks, 41 (71%) had tophi at baseline. By week 13 of the 24week trial, 45% had achieved partial or complete tophus resolution. By week 50, 26 weeks into the extension trial, 90% of the subjects had achieved complete or partial tophus

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resolution (78% of all tophi had complete resolution; p<0.006 from baseline). The outcomes were similar at weeks 78 and 102. The investigators reported three infusion reactions after 609 infusions in the 24-week trial, and three infusion reactions after 810 infusions in the extension trial (24-120 wks).

Among the 35 persistent responders entering the open-label extension, 19 chose to receive pegloticase therapy 8mg every two weeks.

Investigator and presenter, Lee Simon, MD, Head Regulatory Consultant at Leerink Swann/MEDACorp in Boston, Massachusetts, USA concluded, “Prolonged administration for up to 2.5 years of pegloticase 8mg every two weeks is safe and effective in subjects with persistent normalisation of uric acid.” Pegloticase is approved in the US for the treatment of chronic gout refractory to conventional urate lowering therapy. In May, the manufacturer of pegloticase, Savient Pharmaceuticals, announced that their Marketing Authorisation Application had been accepted for review by European Medicines Agency. The study was supported by Savient Pharmaceuticals.

Risk of cancer is not elevated after anti-TNF treatment for arthritis

RETROSPECTIVE ANALYSIS of data from a national arthritis registry study suggests that newer biologics used to treat arthritis, including infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi) and etanercept (Enbrel) do not, as a group, increase the risk of cancer. “Some studies have suggested that treatment with anti-TNFs may increase an individual’s risk of cancer,” said presenter and investigator Lene Dreyer, MD, PhD, Department of Rheumatology, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. “So our aim was to look at data on long-term use in a large

population using a variety of ant-TNFs, to see whether such treatment in Danish arthritis patients is associated with an increased cancer risk,” she added. The researchers evaluated long-term data from patients in the DANBIO (Danish Biologics) national registry. Of the 13,699 arthritis patients in the registry, 8,101 were anti-TNF naïve and 5,598 had received anti-TNF treatment for either rheumatoid arthritis (n=3,496), psoriatic arthritis (n=670), ankylosing spondylitis (n=858) or other arthritis (n=499). The investigators compared cancer incidence among anti-TNF treated subjects to anti-TNF

naïve subjects, for up to 9 years after individual enrollment in the registry. A total of 313 cancers in both groups appeared during a period of 23,965 person-years. The investigators found that 3% (n=181) of those subjects treated with anti-TNF agents developed cancer within 9 years. The incidence of cancer in anti-TNF treated subjects was the same as that in the anti-TNF naïve subjects, with a relative risk of 1.03 (95%CI, 0.82-1.30). No increased overall cancer risk appeared among males or females, or in specific age groups. The study was supported by grants from the Danish Rheumatism Association and the Danish Cancer Society.

Novel, oral tofacitinib shows efficacy in RA refractory to DMARD therapy

ESEARCHERS REPORT that rheumatoid arthritis patients who are refractory to one or more DMARD (disease-modifying anti-rheumatic drug) achieved reduced signs and symptoms of disease after being treated with the investigative, oral JAK (Janus kinase) inhibitor tofacitinib (formerly tasocitinib, CP-690550, Pfizer). Joel Kremer, MD, Chief of Medicine at Albany Medical College in Albany, New York, USA presented first results from a 12-month, Phase III trial. He said that both doses of the drug, 5mg twice daily and 10mg twice daily, were superior to placebo for all primary endpoints. The investigators enrolled 792 rheumatoid arthritis patients refractory to DMARD treatment (81.4% female, ages ranging between 50.853.3 years). Of these subjects, 315 received tofacitinib 5mg twice daily, 318 received 10mg twice daily and 159 received placebo. At month three, all placebo subjects were blindly advanced to tofacitinib 5mg twice daily (n=79) or 10mg twice daily (n=80). At month six, all were blindly advanced to the final six-month phase of the study, but no subjects received a change in study medication. Subjects received concurrent non-biologic

background therapy with DMARDs. Dr. Kremer reported that, after six months of therapy, 52.7% of the 315 patients on the 5mg twice daily dosing achieved an ACR20, the American College of Rheumatology criteria for 20% clinical improvement of symptoms, and the first primary endpoint of the trial. And, 58.3% of the 318 patients on the 10mg dose of tofacitinib achieved an ACR20. The researchers reported that 31.2% of the 159 patients who began therapy on placebo achieved an ACR20. For the second primary endpoint, he reported that, at six months, more patients on tofacitinib achieved clinical remission of disease, measured by lower than a 2.6 score on the Disease Activity Score, using the erythrocyte sedimentation rate (DAS28-4 [ESR]). Only 2.8% of the placebo subjects achieved remission compared to 11% of the 5mg twice daily subjects (P=0.001) and 14.8% (P<0.0001) of the 10mg twice daily subjects. For the third primary endpoint, the investigators also evaluated changes from baseline to month three in the HAQ-DI Health Assessment Questionnaire Disability Index (HAQDI). Tofacitinib 5mg twice daily subjects achieved a 0.46 decline in scores, and 10mg twice daily subjects achieved at 0.56 decline. Placebo

patients achieved a 0.21 decline. For secondary endpoints, the researchers used the ACR50 and ACR 70. They found that 33.8% of patients on 5mg twice daily tofacitinib, and 36.6% of those on the 10mg twice daily tofacitinib treatment, achieved ACR 50 compared with 12.7% of placebo subjects. Also, 13% of lower dose subjects and 16% of the higher dose subjects achieved ACR70, compared with 3.2% of placebo patients (P<0.0001 for both doses). For the 12-month safety analysis, Dr. Kremer said that four subjects had died during the trial, one from a serious cardiovascular event. But the adjudication committee found no relationship between the cardiovascular death and treatment with the drug. Dr. Kremer reported that one of the deaths might have been related to treatment-related infections, but the patient’s family refused to have an autopsy, leaving open the question of the exact cause of death. Four drug-related opportunistic infections appeared during the 12-month trial, two cases of tuberculosis, one case of pneumonia and one case of herpes. All subjects responded well to treatment. The study was sponsored by Pfizer.

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

With over 20,000 clinicians, researchers and industry representatives in attendance, the American College of Cardiology 60th Annual Scientific Sessions took place in New Orleans in April. Highlights from the meeting follow.

Angioplasty is non-inferior to CABG in some patients

NGIOPLASTY WITH A sirolimuseluting stent is non-inferior to coronary artery bypass surgery (CABG) in patients with unprotected left main coronary artery (ULMCA) disease - for rates of death, myocardial infarction, stroke and ischaemia-driven target vessel revascularisation. Researchers presented these findings from the PRECOMBAT (Premier of randomised Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) trial recently at the American College of Cardiology (ACC) 60th annual scientific sessions. “The PRECOMBAT findings suggest that PCI [percutaneous coronary intervention] with a sirolimus-eluting stent appears to be a potential alternative to CABG with a non-inferior incidence of two-year MACCE [Major adverse cardiac and cerebrovascular events] for patients with ULNCA stenosis,” said lead investigator and presenter Seung-Jung Park, M.D., Ph.D, professor of medicine at the University of Ulsan

College of Medicine in Seoul, Korea. The investigators randomised 600 patients to either CABG (n=300) or angioplasty with the sirolimus-eluting Cypher® stent (n=300). They conducted post-intervention, clinical follow-up at 30 days, and six, nine and 12 months. They conducted angiographic follow-up at 8-10 months for the angioplasty group. Baseline characteristics were similar between the groups. The primary endpoint was MACCE at 12 months, which included death from any cause, heart attack, stroke and ischaemia-driven target vessel revascularisation (TVR). Major inclusion criteria were: >/= 18 years of age, significant de novo ULMCA stenosis (>50%), left main lesion and lesions outside ULMCA (if present) potentially comparably treatable with PCI and CABG as determined by physician and operators, and objective evidence of ischaemia or ischaemic symptom with angina or Non-ST Segment Elevation Myocardial Infarction (NSTEMI).

The investigators reported that angioplasty with a sirolimus-eluting stent was not inferior to CABG for composite MACCE scores at 12 months, with rates of 8.7% and 6.7% respectively (p=0.0001; HR 1.29, 95% CI, 0.72 – 2.32). At 24-months, the rates were comparable at 12.2% for angioplasty and 8.1% for CABG. In breaking down MACCE data, the investigators found a significant difference in rates of ischaemia-driven TVR at 24 months, at 9.0% for angioplasty and 4.2% for CABG (p=0.022). Dr. Park noted that the incidences of death, heart attack and stroke, which indicate safety and significantly affect mortality, were not significantly different between the two study groups. He emphasised that the TVR finding did not have a greater direct implication for safety than the other MAACE outcomes. The PRECOMBAT trial was funded by the Cardiovascular Research Foundation (Seoul, Korea), Cordis, and a grant from the Korean Ministry of Health.

Combination drug treatment for obesity improves cardiometabolic risk markers

OMBINATION NALTREXONE/ bupropion (NB) for obesity improves multiple markers of cardiometabolic risk as well as inducing sustained and meaningful weight loss. Researchers reported this finding recently at ACC. “We not only saw a treatment-related and significant reduction in weight among naltrexone/ bupropion-treated patients, but we also saw no significant changes in blood pressure and heart rate,” said lead investigator

and presenter Jorge Plutsky, MD, cardiologist and Director of the Vascular Disease Prevention Program at Brigham and Women’s Hospital in Boston, Massachusetts. The purpose of this sub-study of the COR-II (Contrave Obesity Research) Phase III trial was to evaluate effects of NB (compared to placebo) on markers of cardiometabolic risk, blood pressure (BP), heart rate (HR), and circadian blood pressure patterns in overweight and obese subjects. COR –II was a multicentre,

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randomised, double-blind, placebo-controlled, Phase III study. The investigators analyzed data on 1,496 subjects with a BMI >/=30 and </=45kg/m2 and uncomplicated obesity, or BMI>/=27 and </=45kg/m2 and controlled hypertension and/or dyslipidaemia. Subjects were randomised to NB or placebo (PLB, 2:1 ratio). All subjects received ongoing diet instruction, advice on behaviour modification and exercise counselling.

Patients receiving drug-eluting stents for saphenous vein graft lesions have less revascularisation

ESEARCHERS REPORT that, for rates of revascularisation at one year, drug-eluting stents (DES) appear to be superior to bare metal stents (BMS) in saphenous vein graft lesions.

Out to 12 months, the need of revascularisation was reduced by about half with drug-eluting stents compared to bare metal stents.

The results of the ISAR-CABG (Efficacy Study of Drug-eluting and Bare Metal Stents in Bypass Graft Lesions) study were presented recently at the ACC. “Out to 12 months, the need of revascularisation was reduced by about half with drug-eluting stents compared to bare metal stents, and, for safety parameters, drugeluting stents were comparable to bare metal stents for stent thrombosis, death or myocardial infarction,” said presenter and investigator

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Baseline characteristics for NB and placebo groups were similar for age, sex, race, weight, BMI, dyslipidaemia and hypertension. The primary endpoint of the sub-study was change from baseline to week 52 in average 24-hour systolic blood pressure (SBP) and diastolic blood pressure (DBP). For the ambulatory BP monitoring (APBM) sub-study of COR-II, investigators enrolled 182 of the 1,496 subjects. Monitoring in the substudy took place for most subjects between 7:00am and 10:00am prior to intake of morning medications or study drug.

Julinda Mehilli, MD, director of clinical research and data coordinating in the Intracoronary Stenting and Antithrombosis Research Centre (ISAR) at the German Heart Centre in Munich, Germany. The multi-centre, randomised study was the largest to-date comparing DES to BMS in the saphenous vein. The investigators enrolled 610 subjects who had undergone CABG and who had developed at least one lesion in their saphenous vein graft. They were randomised to angioplasty with DES (n=303) or BMS (n= 307). Baseline clinical and angiographic characteristics were similar between the two groups. The primary endpoint was a composite score of death, myocardial infarction and ischaemiarelated target lesion revascularisation at 1-year post index PCI. For the primary endpoint, Dr. Mehilli reported that, out to 1 year, the incidence of major cardiac events was, significantly, 35% less in the DES group compared to the BMS, with 15.4% of DES subjects having such an event compared to 22.1% in the BMS group (p=0.03). She noted that target lesion revascularisation caused much of the difference in primary outcome, with a 7.2% rate in the DES group compared with 12.9% in the BMS group (p=0.20). There were no significant differences in the

rates of death or myocardial infarction between the groups (Death: DES 5.2% vs. BMS 4.7%, p=0.82. Myocardial infarction: DES 4.2% vs. BMS 6.0%, p=0.27. Combination death and Myocardial infarction: DES 8.5% vs. BMS 10.9%, p=0.27). Dr. Mehilli concluded that while saphenous vein graft lesions remain a challenge for treatment , it is now possible to say that DES are comparable to BMS in terms of the major safety signals of stent thrombosis, death and myocardial infarction. The study was investigator derived.

Monitoring was completed approximately 24 hours later. The researchers reported that changes from baseline to week 52 in average 24-hour blood pressure and pulse were as follows: NB: -0.2mmHgSBP, +0.8mmHgDBP, +0.1 beats per minute (bpm), and PLB: -2.8mmHgSBP (P=0.08 vs NB), -2.1mmHgDBP (P<0.01 vs NB), -0.5bpm (p=0.64 vs NB). They also reported maintenance of normal circadian variation of BP, including a >10% change between daytime and nighttime BP in NB-treated subjects. Weight loss with NB was greater at week 52 for NB than placebo and was sustained out to week 52. A greater proportion of

NB-treated subjects lost >/=5%, >/=10% or >/=15% of their baseline body weight compared to placebo-treated subjects (OR 4.7, 5.8 and 4.3, respectively). NB treatment was generally well-tolerated, and adverse events were consistent with those which were previously reported in naltrexone and buproprion studies. Dr. Plutsky added that, given the growing epidemic of obesity, availability of naltrexone/bupropion could provide a useful tool for physicians and patients who are currently challenged with very limited pharmacotherapeutic options. The study was supported by Orexigen Therapeutics, Inc.

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

Therapeutic hypothermia can be effectively used in younger cardiac patients

OUNG ADULT PATIENTS who suffer from genetic heart diseases like hypertrophic cardiomyopathy (HCM) appear to benefit from therapeutic hypothermia, researchers reported at the American College of Cardiology (ACC) Scientific Sessions in New Orleans, recently. As background, the researchers noted that, in spite of rapid cardiopulmonary resuscitation (CPR) with defibrillation, patients with HCM have particulary low rates of survival following out-of-hospital cardiac arrest. “Therapeutic hypothermia is an effective survival and neuroprotective treatment strategy increasingly employed in unconscious patients with out-of-hospital cardiac arrest and restored spontaneous circulation,” said senior author Barry J. Maron, MD, director of the Hypertrophic Cardiomyopathy Center at the Minneapolis Heart Institute Foundation in Minneapolis. “However, there are no reports of therapeutic hypothermia employed in the

patients with HCM.” The researchers retrospectively analysed patient records at Minneapolis Heart Institute at Abbott Northwestern Hospital in Minneapolis, Minnesota and at Tufts Medical Center in Boston, Massachusetts. They found that seven young, asymptomatic patients with HCM (mean age 43), unexpectedly incurred cardiac arrest within a 46-month period, and survived after receiving therapeutic hypothermia. “This success rate was unexpectedly high, especially given the experience with HCM and the CPR/defibrillation era,” Maron said. The researchers noted that the response was prompt at both facilities, including: collapse to resuscitation within three minutes; transport from collapse to the hospital for initiation of cooling (mean of 172 minutes); and the initial Glasgow coma score was three in each patient. Therapeutic hypothermia was administered with rapid cooling to 31° to 33°

Celsius core body temperature for 24-29 hours, with intact cardiac function and complete restoration of normal neural, cerebral and cognitive functions six to 52 months after the event.

“Therapeutic hypothermia is an effective survival and neuroprotective treatment strategy increasingly employed in unconscious patients with out-of-hospital cardiac arrest and restored spontaneous circulation.” Barry J. Maron

They noted that while reversible complications occurred, all subjects survived with neuroprotection, preserved cognitive function and intact cardiac function six to 52 months after their event. Hypothermia was successful in spite of HCM risk factors such as marked left ventricular wall thickness of more than 20mm in six patients, outflow obstruction, asystole initially in one patient and a long delay to cooling of more than four hours in one patient. “These findings support the idea of more widespread availability and utilisation of therapeutic hypothermia, due to its successful outcomes with out-of-hospital cardiac arrest,” Maron concluded. “Previous research of therapeutic hypothermia has focused on older patient populations, but this study proves the worth of this technique in younger patients with genetic disease.”

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Diabetes UK Reports from Diabetes UK 2011, London by Maria Dalby

To pump or not to pump? by John Pickup, King’s College London School of Medicine. Peter Hammond, Harrogate and District NHS Foundation Trust and Gill Morrison, Royal Liverpool University Hospital

ONTINUOUS subcutaneous insulin infusion (CSII) – insulin pump therapy – is superior to multiple daily injections in a number of respects. In the opening plenary of the Diabetes UK Annual Professional Conference 2011, Professor John Pickup from King's College London argued that the clinical evidence supports wider use of insulin pump therapy than is currently seen within the NHS. The National Institute for Health and Clinical Excellence recommends the use of CSII in adult Type 1 diabetics with persistent disabling hypoglycaemia and/or HbA1c levels ≥8.5% despite optimal MDI therapy, and in children with Type 1 diabetes for whom MDI may not be

possible.1 The clinical evidence base shows that CSII is significantly more effective for preventing severe hypoglycaemia compared with MDI in both adults and children. A meta-analysis of 22 clinical studies published in 2008 showed an overall reduction in the incidence of severe hypoglycaemia of 75% with CSII vs MDI, with the greatest reduction seen in patients with the most severe hypoglycaemia on MDI and those with the longest duration of diabetes.2 This meta-analysis also showed a significant reduction of HbA1c when switching to CSII (0.62% difference; 95% CI 0.47, 0.78); again

this difference was more pronounced in those patients with the poorest control on MDI. This confirmed previous findings of superior glycaemic control with CSII even when MDI therapy was intensified in an attempt to improve control.3 CSII therapy reduces withinand between-day blood glucose variability;4 clinical studies have also shown superiority of CSII over MDI when using glargine-based insulin therapy.5,6 Patients, too, tend to be satisfied with their insulin therapy to a greater extent with CSII compared with MDI. A randomised controlled study carried out across centres in the Netherlands showed a mean reduction of HbA1c levels of 0.84% (95% CI 1.31, 0.36%) at 16 weeks, which was associated with significant improvements on the subscales 'general health' and 'mental health' of the SF-36 tool for assessing health-related quality of life.7 However, whilst the switch to CSII may seem deceptively simple – a matter of just ‘pressing a button’ – Peter Hammond from Harrogate issued a note of caution in his presentation. The full benefit of CSII over MDI may be difficult to achieve in real life, due to the complexity of the pump system itself and its deployment. All pumps currently on the market require at least level 2 numeracy skills for effective operation.8 Harrogate is one of the UK’s leading centres for CSII therapy, and the Harrogate Insulin Pump Users Survey 2011 comprised patients who have used CSII for up to 11 years. Whilst the survey indicates that patients overall achieve good metabolic control with relatively few complications, individual variation is high. To

realise the full potential of CSII therapy, the patient must have a good basic understanding of insulin therapy and be highly motivated to make the educational effort required. The plenary session on CSII therapy was concluded by Gill Morrison from Liverpool, who pointed out the ethical dilemmas that may arise from making CSII available to some patients but not to others, as recommended by NICE.1 Whilst there are patients who are suitable

All pumps currently on the market require at least level 2 numeracy skills for effective operation.

candidates for CSII due to frequent hypoglycaemia, wide blood glucose fluctuations, diabetic complications such as dialysis, or other factors such as an unpredictable lifestyle or pregnancy, there are likewise patients who are highly unsuitable for CSII. These include patients with poor compliance for various reasons, patients who are poorly motivated or who have mental health issues, patients with inappropriate selfcare and those who are physically incapacitated. The NICE recommendations are provided with the aim of encouraging positive outcomes and promoting clinical excellence, whilst at the same time underlining the responsibility of the healthcare professional to make decisions appropriate for the individual patient. As we stand on the threshold of NHS reform with GPs taking responsibility for funding in many parts of the country, trusts will come under increasing pressure to find new funding streams to enable an equitable provision of evidence-based diabetes care. References are available on request.

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Diabetes UK Reports from Diabetes UK 2011, London by Maria Dalby

The science behind the glycaemic index its role in diabetes and obesity management by Jeya Henry, Oxford Brookes University

LOW GLYCAEMIC index (GI) diet may hold the key to controlling blood glucose levels and achieving and maintaining sustained weight loss in patients with Type 2 diabetes. Recent research indicates that the type of carbohydrates we eat may have a greater impact on weight gain and glycaemic control than previously thought. Low-GI food ingredients, developed in close collaboration between food technologists, nutritionists and physicians, is a growing market and may alter the way Type 2 diabetes is managed in the near future. Professor Jeya Henry is director of the Functional Food Centre at Oxford Brookes University, a facility at the forefront of the research into modulating blood glucose and controlling body weight with the help of a low-GI diet. The concept of the glycaemic index – defined as a means of ranking foods on a scale according to the extent to which they raise blood glucose levels when ingested – first appeared in the medical literature in 1981.1 As a general rule, carbohydrate rich foods that break down quickly during digestion have high GI values (70 or over), such as white bread, corn flakes, white rice and potatoes, whereas carbohydrates that break down slowly and gradually release glucose into the blood stream have low GI values (55 or below), including fruit, vegetables and wholemeal bread. Professor Henry’s department at Oxford Brookes University has to date determined the GI of over 600 food products and maintain the largest GI database in Europe. A number of studies have established the link between GI and obesity, and the evidence base is expanding continuously. A study published in 2003 showed that children aged nine to 12 years who ate a low-GI breakfast (with or without the addition of sucrose for palatability) had significantly lower energy intake at lunchtime compared with children who ate a

high-GI breakfast.2 A similar study in children aged eight to 11 years suggested that the reduction in energy intake following a low-GI breakfast may persist for up to three days.3 Making dramatic dietary alterations is a daunting prospect for most people; however, the impact of GI is such that even small changes may have a significant impact. A study carried out at the Oxford Brookes University on young adults who underwent continuous blood glucose monitoring showed that merely replacing white bread with a type of multi-seed bread known as All-In-One at breakfast markedly stabilised blood glucose levels over 24 hours. Food additives to lower GI constitute an emerging and fast-growing market for the food industry. Professor Henry and co-workers have been involved in the development of Fruit Up®, a sweetener derived from carob pods which is used as an alternative to sucrose in food such as drinks, yoghurts and snack bars. Other sweetening agents that have been documented as low-GI alternatives to sucrose include maltitol4 and isomaltulose.5 Beta-glucan is a soluble dietary fibre derived from cereals such as barley; data shows that adding betaglucan can reduce the GI of food products by up to 43%.6 With all due deference to novel food additives and technologies, adopting a low GI diet may simply be about making wise choices with regards to everyday foods. Pulses have low GI due to relatively thick cell walls that are resilient against cooking, unlike potatoes which contain very little protein or cell wall material other than starch and have thick cell walls that easily soften during cooking. A particularly low GI food is peanuts (GI 14) because of its extremely thick and resilient cell walls that enclose very limited amounts of starch. Whilst a freshly baked potato displays a glycaemic response profile almost identical to

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that of pure glucose, the GI of the baked potato as a meal may be nearly halved by adding cheese; baked beans and tuna also reduce the GI but not as effectively as the cheese topping.7 The emerging evidence of the importance of GI is such that researchers are increasingly suggesting that refined carbohydrates are a greater threat to metabolic health than saturated fat.8 Concluding his presentation, Professor Henry stressed the importance of making GI databases available to all health practitioners involved in diabetes care in the UK, as a low GI diet is increasingly looking like a viable option for the long-term management of Type 2 diabetes alongside appropriate drug therapy. References: 1. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr 1981; 34(3): 362-366 2. Warren JM, Henry CJ, Simonite V. Low glycemic index breakfasts and reduced food intake in preadolescent children. Pediatrics 2003; 112(5): e414 3. Henry CJ, Lightowler HJ, Strik CM. Effects of longterm intervention with low-and high-glycaemicindex breakfasts on food intake in children aged 8-11 years. Br J Nutr 2007; 98(3): 636-640 4. Pratt M, Lightowler H, Henry CJ, et al. No observable differences in glycemic response to maltitol in human subjects from 3 ethnically diverse groups. Nutr Res 2011; 31(3): 223-228 5. Holub I, Gostner A, Theis S, et al. Novel findings on the metabolic effects of the low glycaemic carbohydrate isomaltulose (Palatinose). Br J Nutr 2010; 103(12): 1730-1737 6. Thondre PS, Henry CJ. High-molecular-weight barley beta-glucan in chapatis (unleavened Indian flatbread) lowers glycemic index. Nutr Res 2009; 29(7): 480-486 7. Henry CJ, Lightowler HJ, Kendall FL, Storey M. The impact of the addition of toppings/fillings on the glycaemic response to commonly consumed carbohydrate foods. Eur J Clin Nutr 2006; 60(6): 763-769 8. Hu FB. Are refined carbohydrates worse than saturated fat? Am J Clin Nutr 2010; 91(6): 15411542

Islet cell transplantation in the UK by James Shaw, Newcastle University and Peter Jones, King’s College London

SLET CELL transplantation offers a potential of achieving normal glucose levels and preventing hypoglycaemia in patients with Type 1 diabetes, without most of the risks associated with transplantation of the whole pancreas. However, each islet cell transplant requires a large number of cells to have a chance of success, and at the moment the demand exceeds the supply on a vast scale. In his overview of the success of islet cell transplantation in recent years, Professor James Shaw from Newcastle reminded the audience that until recently, transplantation of the whole pancreas offered the only real option of a cure for Type 1 diabetes; however, this involved major abdominal surgery with a mortality rate of up to 5%, and the need for life-long immunosuppression to maintain graft function. The first report of successful transplantation of purified human islet cells in Edmonton, Canada was published in 2000.1 Shortly afterwards the UK Islet Transplantation Consortium (Diabetes UKITC) was formed, and following trials at centres around the UK, the NHS Islet Programme which commenced in April 2008 became the first public health service-funded islet cell transplantation programme in the world. To date, a total of 24 patients have received 36 grafts, with no mortality and a primary graft function rate of 96%. All patients have achieved complete resolution of severe hypoglycaemia, and one in three patients has achieved insulin independence. A number of studies are currently ongoing to evaluate qualitative patient-reported outcomes, and to identify biomarkers for pre-transplant assessment for use with marginal donors and expand the role of islet cell transplantation as a model of autoimmunity and Type 1 diabetes. Whilst the benefit of islet cell transplantation is undisputed, the fact remains that each recipient will require up to one million islets from two or three donors. At present there are approximately 100,000 patients in the UK on the waiting list; with a current availability of approximately 1,000 donors meeting the criteria for islet cell transplantation (heart-

beating, brain-dead) it is clear that this will remain a huge unmet medical need unless alternative sources are found. Outlining the options explored to date, Professor Peter Jones presented results from research into generating human beta cells in vitro, and from using islets from other species. Human beta cells are unable to proliferate in vitro and it is therefore not possible to obtain insulin-producing beta cells in this way.2 The finding that the pancreas is capable of regenerating beta cells out of alpha cells3,4 has been the rationale for attempts to transdifferentiate non-beta cells into islet substitutes;5,6 to date, this research has only been carried out in animal models and its adaptability to humans is not known. Experiments with embryonic and pluripotent adult stem cells have made rapid progress over the last five years and have shown that human beta cells created from stem cells can reverse hyperglycaemia in animal models;7 however, no clinical trials have been performed to date and the reproducibility of the protocol has not been shown.8 In addition, concerns have been raised about the safety of induced pluripotent stem cells due to the risk of mutations.9,10 Xenotransplantation using pig islets has been shown to result in normal islet function in vivo in primates. A Phase I/IIa study in 14 patients with Type 1 diabetes is currently in progress and will be completed in 2013. In Professor Jones’ estimation, provided the outcomes of the clinical trial show safety and efficacy comparable with current insulin replacement

therapy, this technology could be in clinical use within the next ten years. Reference: 1. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343(4): 230-238 2. Parnaud G, Bosco D, Berney T, et al. Proliferation of sorted human and rat beta cells. Diabetologia 2008; 51(1): 91-100 3. Thorel F, Népote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 2010; 464(7292): 1149-1154 4. Chung CH, Hao E, Piran R, et al. Pancreatic β-cell neogenesis by direct conversion from mature αcells. Stem Cells 2010; 28(9): 1630-1638 5. Zhou Q, Brown J, Kanarek A, et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455(7213): 627-632 6. Yechoor V, Liu V, Paul A, Lee J, Buras E, Ozer K, Samson S, Chan L. Gene therapy with neurogenin 3 and betacellulin reverses major metabolic problems in insulin-deficient diabetic mice. Endocrinology 2009; 150(11): 4863-4873 7. Kroon E, Martinson LA, Kadoya K, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008; 26(4): 443-452 8. Matveyenko AV, Georgia S, Bhushan A, Butler PC. Inconsistent formation and nonfunction of insulinpositive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats. Am J Physiol Endocrinol Metab 2010; 299(5): E713-E720 9. Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 2011; 471 7336): 63-67 10.Lister R, Pelizzola M, Kida YS, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 2011; 471(7336): 68-73 11.Hecht G, Eventov-Friedman S, Rosen C, et al. Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model. Proc Natl Acad Sci USA 2009; 106(21): 8659-8664

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 E V I D E N T I A • V O L U M E 5 • I S S U E 3 • J U N E / J U LY 2 0 1 1

European Congress on Osteoporosis and Osteoarthritis Meeting highlights from the ECCEO, Valencia by Bruce Sylvester

In March, over 5,500 participants gathered in Valencia, Spain from around the world for the European Congress on Osteoporosis and Osteoarthritis (ECCEO). ECCEO is the largest, annual event in Europe presenting new clinical research in osteoporosis and osteoarthritis. Highlights from the presentations follow.

Strontium ranelate superior to bisphosphonates for bone formation in post-menopausal osteoporosis

ONE-FORMING activity was signficantly higher in postmenopausal women treated with strontium ranelate compared to those treated with alendeonate, and the therapeutic effect increased up for to 12 months of treatment, researchers reported at ECCEO. The findings come from the largest to-date bone biopsy (histomorphometric) study of strontium ranelate versus alendronate in osteoporosis in women. Investigator and presenter Roland Chapurlat, MD, PhD of Hopital Edouard Herriot in Lyon, France, said “Bone formation in strontium ranelate patients increased all of the time from six to 12 months.”

Investigators in the double-blind, randomised 387 postmenopausal women with osteoporosis to treatment with strontium ranelate 2g/day (n=256) or alendronate 70mg/week (n=131). Each subject had transiliac bone biopsies at baseline and after six months or 12 months of treatment. The investigators obtained 785 bone biopsies, and 84% were evaluable. Of these, they created a total of 268 paired biopsies, 179 for strontium ranelate (90 for six months and 89 for 12 months) and 89 for alendronate (43 for six months and 46 for 12 months). Paired biopsies were used in the analysis. Baseline patient characteristics (age, lumbar

score and duration of menopause) were similar between the paired subjects. The primary endpoint of this study was mean difference between treatment groups (strontium ranelate minus alendronate) for mineralising surfaces after six or 12 months.

“Most drugs we use in osteoporosis treat bone degradation, but strontium ranelate is helpful in increasing some degree of bone formation.” Dr. Cahrpulat.

Dr. Charpulat reported that, after six months, mineralising surface expressed as a percentage of bone surface, or MS/BS, was 2.94% in strontium ranelate subjects compared to 0.20% in alendronate subjects, a highly statistically significant between-group difference of 2.73% (p<0.001). The comparative treatment effect of strontium ranelate increased to 4.65% (p<0.001) after 12 months, with subjects achieving MS/BS values of 4.91% for strontium ranelate vs 0.28% for alendronate. “Most drugs we use in osteoporosis treat bone degradation, but strontium ranelate is helpful in increasing some degree of bone formation,” said Dr. Cahrpulat. “This translated into better bone health for these patients.” The research was sponsored by Servier.

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Nitroglycerin gel increases bone turnover in postmenopausal osteoporosis

ITROGLYCERIN GEL (NTG) therapy uncouples bone turnover, improves bone mineral density (BMD), bone geometry and indices of bone strength, researchers reported at the ECCEO. “Given the findings of this 2-year, randomised trial, the efficacy of nitroglycerin to reduce fracture risk should now be tested in a large clinical trial,” said lead investigator and presenter, Sophie Jamal, PhD, Assistant Professor of Medicine at the University of Toronto in Ontario Canada. The trial lasted 24 months and was blinded. The investigators sought to compare effects once daily administration of NTG ointment (15mg/day) or placebo in postmenopausal women with BMD T-scores between 0 and -2.0 at the lumbar spine and above -2.0 at the hip. The study had a one-week run-in phase, and

the primary endpoint was bone turnover. Inclusion criteria were: female, postmenopausal, >/= 50 years old and lumbar spine T-score between 0 and -2.0. The investigators enrolled 243 women, and 113 (89%) of the 127 nitroglycerin-treated women and 107 (92%) of the 116 placebotreated produced evaluable data at 24 months. For the primary endpoint, Dr. Jamal reported that, compared with placebo, nitroglycerin ointment increased spine BMD by 6.7% (95% CI, 5.2 to 8.2; p<0.001), femoral neck BMD by 7.0% (95% CI, 5.5 to 8.5; p<0.001) and total hip BMD by 6.2% (95% CI, 5.2 to 7.3; p<0.001). For secondary endpoints, she reported that, compared to placebo, nitroglycerin treatment increased cortical thickness (13.9% and 24.6%), periosteal circumference (7.4% and

2.9%), cortical area (10.6% and 10.0%), polar section modulus (10.7% and 9.8%), and polar moment of inertia (7.3% and 14.5%) at the radius and tibia respectively (all p<0.001). Compared to placebo, nitroglycerin also increased bone specific alkaline phosphatase by 36% and decreased urinary N-telopeptide levels by 51%. (p<0.001). Dr. Jamal noted that during the run-in week 104 of 400 recruited potential subjects discontinued, largely due to nitroglycerinassociated headaches. During the subsequent 2-years of the trial, 23.3% of the nitroglycerintreated subjects reported headaches. There were no other unexpected adverse events in the trial. The study was funded by the Canadian Institute of Health Research and the Physicians’ Services Incorporated.

Annual high-dose vitamin D linked to increased falls and fractures in elderly women

NNUAL HIGH-DOSE treatment with vitamin D3 is associated with an increase in falls and fractures among older women, researchers reported at ECCEO. “Surprisingly, the falls were 15% higher in the vitamin D group compared with the placebo group. And this was a significant difference,” said presenter and lead investigator Kerrie M. Sanders, PhD, associate professor at the University of Melbourne, Australia. The study was randomised, placebocontrolled and double blind. Eligibility included female sex, age 70 or older and residence in a community-dwelling environment. The subjects received a single annual dose of cholecalciferol 500,000 IU (10 x 50,000 IU tablets) or placebo in the autumn or winter, for three-five years. There were 1,131 cholecalciferol subjects and 1,127 matched

placebo subjects. Median age was 76 years at enrollment. All subjects returned monthly records of falls and fractures, with phone follow-up to complete data collection. Dr. Sanders said that 837 of the women in the vitamin D group reported 2,892 falls (83.4 per 100 person years) compared to the placebo group in which 769 women fell 2,512 times (72.7 per 10 person years.) The incidence rate ratio between the groups was 1.15 (a 15% increase for vitamin D women), 95% CI: 1.021.30 and a significant p-value of 0.03. All fractures were confirmed radiologically. Incidence of both first fall and first fracture were greater in the vitamin D group (hazard ratios; 95% CI: Falls 1.16; 1.05, 1.28 p=0.003; Fractures 1.26; 0.99, 1.59 p=0.057). The investigators identified an increased rate

of falls in the vitamin D group in the first three months following dosing, compared to placebo, (p=0.017). Notably, increased risk of falls and fractures did not change after adjustment of the data for age or calcium intake. Falls with soft tissue injury (with and without fracture) increased in the vitamin D group. Biochemical blood serum analyses were performed in a sub-study of 137 randomlyselected participants. While up-regulation of vitamin D 24 hydroxylase and reduction in serum 1,25D (1,25-dihydroxvitamin D) levels were identified in the vitamin D group, the findings provided no definitive biochemical explanation for the greater incidence of falls and fracture. The study was investigator initiated.

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European Congress on Osteoporosis and Osteoarthritis Meeting highlights from the ECCEO, Valencia by Bruce Sylvester

Combination alendronate/vitamin D3 lowers 25-hydroxyvitamin D insufficiency

OMPARED TO A standard care group, one year of treatment of postmenopausal, osteoporotic women with weekly alendronate plus vitamin D3 5600 (ALN/D5600) led to a reduction in the proportion of patients with inadequate 25-hydroxyvitamin D (25[OH]D). Investigator Jean-Yves Reginster, MD, PhD, Professor and Director, Department of Public Health, Epidemiology and Health Economics, University of Liége, Belgium, presented the finding in a poster presentation recently at the European Congress on Osteoporosis and Osteoarthritis (ECCEO). Vitamin D insufficiency is prevalent among postmenopausal women, and vitamin D supplementation has been associated with higher bone mineral density (BMD) and improved BMD response to therapy with antiresorptive treatment.

Dr. Reginster reported that the investigators found a significantly lower proportion of patients with serum 25-hydroxyvitamin D of less than 20ng/mL after both six months and 12 months of ALN/D5600 treatment, compared to standard care. The goal of the

to ALN/D5600 (n=257) or referred care (n=258). Baseline characteristics included mean age=73 years, 72% Caucasian, mean 25(OH)D=15ng/mL, and 56% with 25(OH)D≤15ng/mL. The subjects received either ALN/D5600

Vitamin D insufficiency is prevalent among postmenopausal women, and vitamin D supplementation has been associated with higher bone mineral density (BMD) and improved BMD response to therapy with antiresorptive treatment.

study was to evaluate the effects on serum 25-hydroxyvitamin D [25(OH)D], bone turnover markers, and BMD in postmenopausal osteoporotic women with low 25(OH)D, following treatment with either weekly combination alendronate 70mg plus vitamin D3 5600IU (ALN/D5600), or by referred care (usual care/drug therapy for osteoporosis from patient’s usual physician, none of whom were investigators in the trial.) The trial was open-label, and investigators were blinded to 25hydroxyvitamin D levels, except when they fell below 6ng/mL and required rescue therapy. Enrollment criteria included age 65 or older, female sex, postmenopausal for one or more years, BMD (bone mineral density) T-score </= -2.5 at one site or </= 1.5 at one site if showing prior fragility fracture. Other criteria were one or more falls in the past year, reduced lower extremity function and serum 25(OH)D of 8-20ng/mL at enrollment. Investigators randomised enrollees

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weekly (plus 500mg elemental calcium daily, if daily intake of ALN/D5600 was less than 1,000mg), or they were referred to their own physicians for osteoporosis treatment. The primary endpoint of the study was the proportion of patients with 25(OH)D<20ng/mL after six and 12 months' treatment. The investigators reported that the proportion of subjects with 25(OH)D<20 at six months was 31.0% for ALN/D5600 vs 8.6% for referred care (p<0.001). At 12 months the proportion of subjects with 25(OH)D<20 was 36.9% for ALN/D5600 vs 11.3% for referred care (p<0.001). For secondary endpoints, the researchers reported that urine NTX (urine N-telopeptides of Type 1 Collagen) reductions for ALN/D5600 vs referred care were -58% and -50%, respectively, and for serum BSAP (Bone Specific Alkaline Phosphatase) were -51% and -43%, respectively. Also, mean changes in BMD were, respectively, 4.9% and 3.9% at lumbar spine and 2.2% and 1.4% at total hip. For one or more falls at 12 months, the researchers reported a hazard ration of 0.82 for ALN/D5600 vs referred care. For two or more falls they reported a hazard ration of 0.93. No new safety signals appeared in the study. The study was supported by Merck.

European Medicines Agency

highlights

by Gary Finnegan

EMA hits back at ‘transparency’ critics

HE EUROPEAN MEDICINES AGENCY has become embroiled in a war of words in the pages of a leading medical journal which published an article accusing the regulator of failing to meet EU transparency standards. The Agency’s acting Executive Director, Andreas Pott, wrote to the British Medical Journal to defend the EMA and highlight its recent efforts to become more transparent. The intervention followed a stinging critique by Peter C Gøtzsche and Anders W Jørgensenl, researchers from the Nordic Cochrane Centre in Denmark, who said doctors cannot make informed decisions about which medicines to choose for their patients because the EMA’s massive bank of clinical trials data remains unpublished. The Nordic Cochrane Centre has been locked in a three-year battle with the EMA in an effort to force the Agency to release unpublished trials. Industry experts say much of the data submitted to the EMA could be considered commercially-sensitive and is provided to the regulator on the understanding that it will remain confidential. Mr. Potts said the article by Gøtzsche and Jørgensenl failed to acknowledge the EMA’s new access to documents policy introduced last November, the opening of the EU Clinical Trials Register, and a public consultation process on the release of safety data held in the EurdraVigilance database. “These policies will strengthen the Agency's approach to proactive and reactive dissemination of information on the quality, safety and efficacy of medicines,” Mr. Potts said. However, others have also weighed into the debate in support of the criticisms levelled by Gøtzsche and Jørgensenl. Formindep, a Francebased group representing health professionals, wrote to the BMJ criticising the agency for not complying with the EU’s decade-old transparency directive. “Our own experience of EMA transparency policy implementation does concur with Mr. Gotzsche and Mr. Jorgensenl's findings,”

according to Formindep, which has lodged a complaint with the European Ombudsman in an effort to force the EMA to publish files relating to the declarations of interests made by the experts it uses to evaluate medicines.

MEPs refuse to endorse EMA accounts The European Parliament has refused to sign off on the accounts of the European Medicines Agency and has criticised its drug approval process. MEPs are required to approve how EU agencies spend their money in what is normally a routine parliamentary procedure. However, the Parliament said in May that they could not endorse the 2009 budget report presented by the medicines agency because they believe there was “no proper guarantee of the independence of experts hired to carry out scientific evaluations of human medicines.” Some EMA experts also had conflicting interests in the case of the evaluation of the anorectic Benfluorex, according to MEPs. The report criticises the EMA’s management of procurement procedures and its lack of criteria for recruiting staff. The Agency has been working to become more transparent in recent years following repeated criticism from the European Parliament and EU Ombudsman. As part of this confidence-building work, the EMA held its first stakeholder forum on the implementation of new pharmacovigilance legislation in April. Participants from industry, patient and healthcare professional representatives, along with national medicines regulatory authorities, met in London to debate the implications of new EU rules which come into force next year.

Green light for new drugs The EMA has recommended that marketing authorisations be adopted for a range of new medicines. The Committee for Medical Products for Human Use (CHMP) adopted positive opinions for the following:

Benlysta (belimumab), from Glaxo Group Ltd, intended as add-on therapy in adult patients with active autoantibody-positive systemic lupus erythematosus with a high degree of disease activity. Vibativ (telavancin), from Astellas Pharma Europe B.V., intended for the treatment of adults with nosocomial pneumonia, known or suspected to be caused by methicillin-resistant Staphylococcus aureus (MRSA). This is the first antibacterial medicine to receive a positive CHMP opinion in two years, albeit in a restricted indication, addressing an increased need for new antibiotics. Victrelis (boceprevir), Merck Sharp & Dohme Ltd, intended for the treatment of chronic hepatitis-C genotype-1 infection, in combination with peginterferon alpha and ribavirin, in adult patients with compensated liver disease who are previously untreated or for whom previous therapy has failed. The Committee carried out an accelerated assessment of this medicine, because it found that boceprevir could answer the unmet medical need to provide improved treatment options for chronic hepatitis-C genotype-1 naïve as well as pretreated patients. Xgeva (denosumab), from Amgen Europe B.V., intended for the prevention of skeletalrelated events in adults with bone metastases from solid tumours. Yervoy (ipilimumab), from Bristol-Myers Squibb Pharma EEIG, intended for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy.

U-turn on MS therapy The CHMP has reversed its decision on a new multiple sclerosis drug after revisiting its initial ruling. Following re-examination of its previous negative opinion, the Committee adopted recommended the granting of a conditional marketing authorisation for Fampyra (fampridine), from Biogen Idec Ltd. Fampyra is intended to improve walking of adult patients suffering from multiple sclerosis with walking disability.

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Journal reviews by Bruce Sylvester

Reporting from some of the latest articles in

www.nejm.org

Adolescent BMI associated with early onset diabetes and heart disease

EVENTEEN YEARS OF follow-up of 37,000 Israeli teenagers shows that diabetes risk is associated with elevated increased body mass index (BMI) near diabetes diagnosis in early adulthood, and coronary heart disease risk is associated with elevated BMI both at adolescence and adulthood. Researchers published the findings in a recent issue of the New England Journal of Medicine. "The study suggests that the obesity problem in children and teens is likely just the tip of an iceberg for increased risk for Type 2 diabetes and heart disease in adulthood,” said author, Amir Tirosh, MD PhD, of the Endocrine Division at Brigham and Women's Hospital in Boston, Massachusetts. The investigators followed 37,000 Israeli career army members, starting at age 17. They recorded BMI at baseline and every few years. With a mean follow-up period of 17 years, average BMI of the participants rose at a rate of 0.2-0.3 units per year, with an average weight gain of approximately 30lbs between ages 17 and 30. The researchers found that, during the study period, doctors diagosed 1,173 new cases of diabetes and 327 new cases of heart disease. Controlling for risk factors such as age, fasting blood sugar, blood lipids, blood pressure, smoking and family history, the investigators concluded that, at age 17, BMI, even in normal range, could predict eventual

onset of both diseases. They found that each rise in one unit of BMI was associated with about a 10% increase in the risk for Type 2 diabetes in early adulthood, and a 12% increase in the risk for heart disease. "Previous studies did not unequivocally confirm the association between pre-adulthood BMI and diseases in early adulthood. This study is significant because it demonstrates that the association exists within the currentlyconsidered normal values for BMI, having distinct effect on two diseases occurring in early adulthood and in an age group that is frequently neglected," said Professor Assaf Rudich, MD, PhD, of the Ben-Gurian University of the Negev, Beer-Sheva, Israel. Notably, subjects at age 17 with a BMI of 23.4Kg/m2 or higher were at significantly elevated risk for eventually developing diabetes; the same was true for heart disease for BMI 20.9Kg/m2 or higher (163lbs or 146lbs in a 5'10" male teenager, respectively). For diabetes, BMI at age 17 was predictive of risk because it is associated with BMI later in life. But for heart disease, BMI at adolescence and BMI at adulthood independently predicted onset risk. "For prevention of early occurrence of heart disease in adulthood it would seem that very early intervention to promote healthy life-style habits is warranted, even during childhood," Dr. Tirosh said.

www.jama.ama-assn.org

Researchers warn about posthysterectomy oestrogen therapy

N AN EDITORIAL in the recent issue of JAMA/ Journal of the American Medical Association the authors caution against the use of oestrogen-only hormone therapy in women who have had a hysterectomy, noting evidence showing that it raises the risk of breast cancer. Editorial writers Graham Colditz, MD, PhD, and Emily Jungheim, MD, both of Washington University School of Medicine in St. Louis, Missouri, note that even though short-term use of oestrogen-only therapy seems safe, long-term consequences of that short use are unknown. The editorial is a response to a study (published in the same issue) reporting that oestrogen-only therapy in these post-

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hysterectomy patients may decrease breast cancer risk if received for under five years. The researchers found that the negative effects of hormone therapy (HT), primarily stroke, went away after the women stopped treatment. The benefit of a decreased risk of bone fracture also disappeared. And a decreased risk of breast cancer found in the oestrogen-only group continued even after therapy ended. But Colditz and Jungheim asked their readers to consider the larger body of evidence contradicting the breast cancer finding in this one study, evidence that suggests that hormone therapy may raise the risk of breast cancer. Even though oestrogen therapy is usually used on a short-term basis to manage menopausal symptoms after hysterectomy, Colditz and Jungheim question whether there is really a safe duration of use.

The authors caution against the use of oestrogen-only hormone therapy in women who have had a hysterectomy, noting evidence showing that it raises the risk of breast cancer.

The Women's Health Initiative (WHI), which was the source for the study data, began recruiting participants in 1993 and examined risks and benefits of hormone therapy, including oestrogen-only therapy. It was standard practice then to use hormone therapy to treat women with menopausal symptoms "Back then hormone therapy was prescribed almost like a vitamin," said Jungheim. The WHI study ended early due to an increase in stroke risk and the appearance of no clear benefits in other disease categories. In their editorial, Colditz and Jungheim questioned the appropriateness of the WHI population when asking whether oestrogenonly therapy is safe for treating the symptoms of menopause, including hot flushes, mood swings and sleep disturbances. They noted that 68% of the women in the WHI were over age 60 when enrolled in the study, making them older than

the average woman entering menopause. They note that although the women were followed for ten years after therapy stopped, average active use of hormones was only three and a half years. They conclude that the WHI results cannot address the risks and benefits of longer-term oestrogen use. Despite the risks, Jungheim still sees a role for short-term hormone therapy in treating women with severe menopausal symptoms, especially those experiencing premature menopause. "The symptoms women experience around the time of menopause can be significant. There may be a role for hormone therapy for some women who cannot find relief from other things," she said. "But it's worth exploring other options including medications and lifestyle changes."

BMJ www.bmj.org

Excess doses of thyroid drugs can cause an increased risk of fractures

XCESS DOSES OF thyroid drugs can cause an increased risk of fractures, and too many older adults are putting themselves at risk, researchers reported in a study published online recently by the British Medical Journal. As background the authors noted that most hypothyroid patients are diagnosed in early or middle adulthood. With age thyroxine requirements decrease, but dosing of levothyroxine, synthetic thyroxine, is not always decreased. This mismanagement of treatment can induce excess thyroid hormone levels (hyperthyroidism) which can increase fracture risk, especially in older women. Prior research on the association between levothyroxine and fractures had produced inconclusive results. In this new study, Canadian researchers sought to measure the effect of levothyroxine dose on the risk of fractures in older adults. They evaluated retrospectively populationbased data from 213,511 people aged 70 years or older with at least one levothyroxine prescription dispensed in Ontario, Canada between April 1, 2002 and March 31, 2007. They used hospital records to identify fractures, and each case was matched with up to five controls from within the group who had not yet fractured. Cases and controls were defined as current users, recent past users (discontinued 15-180

days prior to study) or remote users (discontinued more than 180 days prior to study) of levothyroxine. They found that 22,236 (10.4%) of the subjects had at least one fracture during the study period. They also found that, compared with remote use, current and recent past levothyroxine use was associated with a significantly higher fracture risk. Among current users, high and medium doses of levothyroxine were associated with a significantly higher risk of fractures compared with low dose levothyroxine. And they found a dose-related association in both men and women, both for hip fractures and for any fracture. The authors concluded, "Our findings provide evidence that levothyroxine treatment may increase the risk of fragility fractures in older people even at conventional dosages, suggesting that closer monitoring and modification of treatment targets may be warranted in this vulnerable population." This conclusion was supported in an accompanying editorial by Professor Graham Leese at Ninewells Hospital in Dundee, UK who said that ideal thyroxine doses may vary with age and be unexpectedly low in elderly people, requiring more research. "With the prevalence of treated hypothyroidism increasing, and the annual economic burden of fractures in the United Kingdom currently estimated at €5.8bn (£5.1bn; $8.4bn), such research warrants a higher priority," he said

www.thelancet.com

Mid-section fat is not more dangerous for heart

ratio) have three times greater risk of heart attack than people with general obesity (as assessed by the body-mass index (BMI), or the weight divided by the height squared). But, they noted, the earlier studies had major design limitations. In the newly-reported research, over 220,000 adults were monitored for almost a decade, and about 14,000 developed a heart attack or stroke during monitoring. The researchers found that that while obesity is a major determinant of cardiovascular disease, body mass index (BMI), waist circumference, and waist-to-hip ratio each had a similar impact on the risk of subsequent heart attack and strokes. Also, BMI, waist circumference, and waistto-hip ratio, whether assessed alone or in combination, did not improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids. The authors concluded, "Whether assessed singly or in combination, body-mass index, waist circumference, and waist-to-hip ratio do not improve prediction of first-onset cardiovascular disease when additional information exists on blood pressure, history of diabetes, and cholesterol measures… This finding applies to a wide range of circumstances and clinically relevant subgroups…The main finding of this study does not, of course, diminish the importance of adiposity as a major modifiable determinant of cardiovascular disease." Sources: Brigham and Women's Hospital, Washington University School of Medicine, BMJ, The Lancet

VALUATING DATA ON 220,000 subjects, researchers concluded that obese persons with fat deposits on the middle section of the body are not at higher risk of heart attacks and strokes than obese persons with other types of fat distribution. The findings appear in a study published online recently by The Lancet. The research was performed by the Emerging Risk Factors Collaboration, a consortium of 200 scientists from 17 countries with leadership from the University of Cambridge, UK. As background, the investigators noted that earlier research suggested that people with "central obesity" (as assessed by the ratio of the waist to hip circumference, or "waist-to-hip" E V I D E N T I A • V O L U M E 5 • I S S U E 3 • J U N E / J U LY 2 0 1 1

Medical news from around the world by Gary Finnegan

World Health Matters CANADA New immigrants less likely to have premature babies RESEARCHERS IN TORONTO have shown that new immigrants are less likely than their Canadian counterparts to have premature babies in their first five years in Canada, but this positive trend declines the longer they stay. The study, conducted at St. Michael’s Hospital, reveals that newcomers have fewer premature births regardless of where they live but their living conditions tend to decline if they stay in poor neighbourhoods. “Living in poor neighbourhoods has been linked with poor health outcomes, but this study shows that this is not always the case for new Canadians,” says Dr. Marcelo Urquia, epidemiologist at the Centre for Research on Inner City Health at St. Michael's Hospital. “For new immigrants, while they have an advantage on avoiding premature births in the early years, they progressively lose it and actually experience an accelerated deterioration when living in deprived urban areas. We need to take steps to make sure new Canadians can find upward socioeconomic mobility when they arrive.” Previous studies have also shown that the longer immigrants stay in Ontario cities, the higher the risk of premature delivery. This study extends these findings and uncovers new data, according to Dr. Urquia. The research shows that once immigrants have lived in Canada for 15 years or more, they have higher premature birth rates than Canadian-born residents living in the poorest neighbourhoods. While the risk of premature delivery increases for most immigrants with time spent in Ontario cities, those who live in poor neighbourhoods experience the highest risk, the study found. “For the first 15 years in Canada, the study found that the maternal country of birth was a better indicator of the risk of premature birth,” says Dr. Urquia. “After that period, the pattern is reversed and immigrants reach the level of inequalities in premature birth observed at the

neighbourhood level among Canadianborn residents.” Published in the Journal of Urban Health, the study reviewed birth data from Ontario hospital records from 2002-2007 and were linked to an official Canadian immigration database for 1985 to 2000. A premature birth involves a baby born that is less than 37 weeks of gestational age and is at much greater risk of short-and long-term complications including disabilities and impediments in growth and mental development.

IRELAND Researchers pinpoint brain region that influences gambling A NEW STUDY HAS uncovered the part of the brain responsible for the risky decisions made by gamblers. Using functional magnetic resonance imaging (fMRI), researchers were able to observe brain activity typical of people gambling in a casino.

“For this particular study, we were interested in what part of the brain might play a role in controlling these strategies that drive behaviour.” Professor John O'Doherty

When a group of gamblers gather around a roulette table, individual players are likely to have different reasons for betting on certain numbers. Some may play a “lucky” number that has given them positive results in the past—a strategy called reinforcement learning. Others may check out the recent history of winning colours or numbers to try and decipher a pattern. Betting on the belief that a certain

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outcome is “due” based on past events is called the gambler’s fallacy. Scientists at Trinity College Dublin, in collaboration with California Institute of Technology (Caltech), say the dorsal striatum drives these different types of decision-making behaviours. “Through our study, we found a difference in activity in the dorsal striatum depending on whether people were choosing according to reinforcement learning or the gambler’s fallacy,” says John O'Doherty, adjunct professor of psychology at Trinity College Dublin. “This finding suggests that the dorsal striatum is particularly involved in driving reinforcementlearning behaviours.” In addition, the work, described in the Journal of Neuroscience, suggests that people who make choices based on the gambler’s fallacy may be doing so because they are not taking into account what they had previously learned or observed. Simulating gambling scenarios was key to working out how the brain deals with such situations. “For this particular study, we were interested in what part of the brain might play a role in controlling these strategies that drive behaviour,” says O'Doherty, who is also professor of psychology at Caltech and conducted the study along with postdoctoral scholar Ryan Jessup. The team asked 31 participants to complete four roulette-wheel tasks while lying in an MRI scanner. For each round, the volunteers at Trinity College were asked to choose a colour on a tricoloured spinning wheel. If the wheel stopped on their colour, they won €2. For each round, participants were charged 50c, regardless of the outcome. All the while, the researchers studied the brain activity of participants, with a focus on how they appeared to choose colours. “The dorsal striatum was more active in people who, at the time of choice, chose in accordance with reinforcement-learning principles compared to when they chose

according to the gambler’s fallacy,” says Jessup. “This suggests that the same region involved in learning is also used at the time of choice.” The two types of strategies are actually contradictory because in reinforcementlearning behaviour, one would be more likely to choose something if it has won a lot recently, and less likely to choose something if it has lost a lot recently. The opposite is true of the gambler’s fallacy. “The task was novel because making decisions based on either reinforcement learning or the gambler's fallacy is not rational in this particular task, and yet most of the subjects acted irrationally,” explains Jessup. “Only 8 out of 31 subjects were generally rational, meaning they simply chose the colour that covered the largest area in that round.” “It is very important to try to understand how interactions between different brain areas result in different types of decision-making behaviour," says O'Doherty. "Once we understand the basic mechanisms in healthy people, we can start to look at how these systems go wrong in patients who suffer from different diseases, such as psychiatric disorders or addiction, that impact their decision-making capabilities.”

AUSTRIA Flu vaccine from cell culture shows promise A FLU VACCINE derived from cell culture is as effective as currently available flu vaccines, but would be less susceptible to manufacturing problems, according to a new Austrian study. By using cell culture, it would also be possible to incorporate that year’s predicted seasonal flu strains into the vaccine much later than is currently possible, reducing the chances of error. The findings, which appear in an article published ‘Online First’ by The Lancet, were reported by Dr. P Noel Barrett of Baxter BioScience, Biomedical Research Centre, Orth an der Donau, Austria. Currently most influenza vaccines are produced using embryonated hens' eggs. This is a cumbersome process and manufacturing difficulties have led to vaccine shortages in the past. Vaccines derived from cell culture are produced in state-of-the-art manufacturing facilities using well-characterised cell lines which are available in unlimited amounts and allow reliable and flexible vaccine supply.

Advocates of cell culture for producing vaccines say the technique overcomes many of the problems associated with the traditional model. In this study, the authors analysed a vaccine derived from Vero-cell-culture. Vero cells are very well characterised and have been used for over 25 years for the production of human vaccines such as polio and rabies, and, more recently also rotavirus vaccine, of which hundreds of millions of doses have been safely used. A randomised controlled phase III trial was carried out in 36 centres, in which healthy adults (aged 18-49 years) were assigned in a 1:1 ratio to one injection of either placebo or Vero-cell-culture-derived influenza vaccine during the 2008-09 season. A total of 7,250 participants were randomly assigned to vaccine (n=3626) and placebo (n=3624). Overall protective efficacy for antigenically-matched influenza infection was 78.5%. The authors say that this compared well with current egg-derived vaccines, with one recent review reporting average protective efficacy of 73% when the vaccine strains matched circulating strains. The new vaccine was well tolerated with no treatment-related serious adverse events. Adverse events were mainly mild and transient. The antibody response (level of antibodies required for protection) produced by the new vaccine was similar to existing vaccines. “Comparison with previously published meta-analyses shows that the Vero-cell-derived seasonal influenza vaccine is at least as immunogenic and efficacious as traditional egg-derived vaccines. Our data also provide the first evidence that correlates of protection established for egg-derived influenza vaccines are also appropriate for cell culture-derived vaccines,” according to the authors.

SOUTH KOREA Study supports post-partum bleeding treatment NEW RESEARCH SHOWS that a minimally invasive radiology treatment for postpartum haemorrhage can help save lives and preserve the uterus. Pelvic arterial embolisation (PAE) is safe and effective treatment, the Society of Interventional Radiology's 36th Annual Scientific Meeting in Chicago heard, based on a

large 225-patient study. 86% of patients included in the trial showed positive results, illustrating that pelvic arterial embolisation has the advantages of being a safe, rapid, economic and repeatable procedure – performed without general anesthesia, according to Dr. Ji Hoon Shin, associate professor with the radiology department, Asan Medical Centre, University of Ulsan College of Medicine in Seoul, South Korea. “Moreover, pelvic arterial embolisation preserves the uterus, allowing resumption of menstruation and preserving fertility. Traditional surgical methods to stem postpartum haemorrhage, such as uterine artery ligation, uterine suturing and hysterectomy, involve the loss of fertility and risks from general anaesthesia,” Dr. Shin said.

“Many obstetricians and gynaecologists know the usefulness of pelvic arterial embolisation over surgery...” Dr. Ji Hoon Shin

“Many obstetricians and gynaecologists know the usefulness of pelvic arterial embolisation over surgery, yet there is not always a connection between them and the interventional radiologist,” explained Shin. He said more doctors should refer patients to an interventional radiologist for treatment, making pelvic arterial embolisation a more popular alternative to surgery. All women who carry a pregnancy beyond 20 weeks' gestation are at risk for postpartum haemorrhage or PPH, which remains one of the major causes of maternal morbidity and mortality throughout the world. “Many case studies have reported on pelvic arterial embolisation’s usefulness for the control of postpartum hemorrhage, yet most of them involved fewer than 100 patients. This study, based on the treatment of 225 patients in a single centre, had an initial clinical success rate of 86%,” Dr. Shin said. While these results are promising, the researchers stressed the need to explore the impact of the treatment on future fertility. And, said Shin, most patients referred for pelvic arterial embolisation had stable blood pressure, so other studies will be forthcoming on the treatment’s role in a clinical setting.

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FDA highlights by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs Statins appear to protect against kidney complications after elective surgery

SE OF A statin before major elective surgery appears to reduce serious post-operative kidney complications, researchers report in study published early online recently by the Journal of the American Society Nephrology.

“Our study suggests that statin use in older persons results in less kidney injury following major elective surgery and reduces the risk of premature death after surgery.” Amber Molnar

Amber Molnar, MD, University of Western Ontario and Lawson Health Research Institute, London, Ontario, and colleagues conducted a population-based retrospective study of all older patients who underwent major elective surgery in the province of Ontario, Canada from 1995 to 2008. Surgeries included cardiac, thoracic, vascular, intra-abdominal, and retroperitoneal procedures. As background, the authors noted that, world-wide, there are over 230 million major elective surgeries performed annually, but many patients who have elective surgeries also experience kidney injury soon after surgery, often due to reduced blood flow to the kidneys and/or inflammation. The investigators evaluated data on 213,347 patients from 211 hospitals who underwent major elective surgery. They found that 4,020 patients (1.9%) suffered postoperative kidney injury within two weeks of surgery, 1,173

patients (0.5%) required dialysis within two weeks of surgery and 5,974 (2.8%) died within one month of surgery. Before surgery, 67,941 patients (32%) were taking a statin. The investigators found that these patients were 20% less likely to develop kidney injury, need dialysis, and die compared with patients who were not taking a statin. They also saw a dose-effect, with higher potency statins causing less kidney injury. Notably, statin use was beneficial whether it began more than 90 days or less than 30-days prior to surgery. “Our study suggests that statin use in older persons results in less kidney injury following major elective surgery and reduces the risk of premature death after surgery,” said Dr. Molnar. She added that the results warrant further investigation with more rigorous studies, but such trials will be difficult to carry out. “Conducting randomised controlled trials to examine whether statins are protective against definitive renal outcomes, such as acute dialysis, will be logistically challenging given that the need for acute dialysis is a relatively rare event,” she said.

Memantine studies don’t yet offer strong evidence for efficacy in mild alzheimer disease

NEW ANALYSIS OF data from clinical studies of memantine has revealed a lack of evidence for efficacy for patients with mild Alzheimer disease (AD) and mild cognitive impairment. Results of the study were published online recently by the Archives of Neurology. “Memantine, indicated for moderate to severe AD, is frequently prescribed off-label either alone or with a cholinesterase inhibitor for mild AD and mild cognitive impairment,” the authors wrote. “There were no significant differences between memantine and placebo on any outcome for patients with mild AD,

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either within any trial or when data were combined,” they added. Lon S. Schneider, MD, University of Southern California Keck School of Medicine, Los Angeles, California, and colleagues conducted a search of manufacturersponsored meta-analyses, registries, presentations, and publications for randomised, placebo-controlled, parallelgroup clinical trials of memantine in patients with mild to moderate AD.

“There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined.” Lon S. Schneider

They identified three eligible trials that included 431 patients with mild AD and 697 patients with moderate AD. They analysed the data for cognition, global change, functional activities, and behaviour. Among patients with moderate AD, there was no significant difference between memantine and placebo in any individual trial. However, they found a significant difference in effect when the three trials were statistically combined, leaving final judgment on the matter open to further study. “Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD, and there is meager evidence for its efficacy in moderate AD,” the authors concluded. “Prospective trials are needed to further assess the potential for efficacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD.”

Combination therapy for weight loss better than other drugs, but side effects remain challenging

OMBINATION PHENTERMINE and topiramate has doubled the weight loss of orlistat, the only drug approved for the long-term treatment of obesity, and its efficacy is comparable to Phase III trial results on other drugs, researchers report. The finding was published online recently by The Lancet. As background, the authors noted that phentermine is the most widely prescribed weight-loss drug in the US, but no long-term randomised trials have evaluated its efficacy and safety. Topiramate is an anticonvulsant medication approved for the treatment of seizure disorders and migraine prevention. In clinical trials of topiramate, obese topiramate patients with Type 2 diabetes and hypertension have achieved significant weight loss, but some have suffered cognitive and psychiatric side effects. The investigators in the new study hypothesised that combination with another drug using lower dosing of topiramate and controlled-release formulation might reduce the incidence of such side effects.

They designed the CONQUER Phase III trial to evaluate the efficacy and safety of the controlled-release combination of phentermine and topiramate in addition to diet and lifestyle changes to promote weight loss in overweight and obese adults with >2 weight relatedcomorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity). Between November 2007 and June 2009, they enrolled 2,487 overweight or obese adults at 93 centres in the US, prescribed standardised counselling for diet and lifestyle changes and randomised the subjects to a once-daily treatment with placebo (n = 994), once-daily controlled-release phentermine 7.5mg and topiramate 46mg (n = 498) or once-daily controlled-release phentermine 15mg and topiramate 92mg (n = 995), all for 56 weeks. They reported that, at 56 weeks, reduction in bodyweight was significantly greater in the groups prescribed both doses of the phentermine and topiramate combination, than in placebo. Mean weight changes were -1.4kg (3lb) for placebo, -8.1kg (18lb) for low dose phentermine and topiramate and -10.2kg (22lb) for high dose phentermine and topiramate. Only 21% of patients achieved 5% weight loss with placebo, compared with 62% in the

lower dose phentermine and topiramate group and 70% in the higher dose group. Phentermine and topiramate treatment was generally well tolerated with dry mouth, constipation, and paraesthesia the most commonly reported side effects.

“Reduction in concomitant use of drugs with phentermine and topiramate suggests that an effective weight loss treatment could reduce the need for treatment of each disease by addressing the underlying pathophysiological changes and obesity-related disease.”

But, the investigators reported a doserelated increase in psychiatric and cognitive adverse events with combination treatment. Discontinuation rates due to adverse events roughly doubled with the higher dose versus placebo, with a smaller increase at the lower dose. “Most importantly, weight loss achieved with phentermine and topiramate was sustained during 56 weeks with improvements in blood pressure, lipids, glycaemia, and inflammatory markers,” the authors wrote. “Reduction in concomitant use of drugs with phentermine and topiramate suggests that an effective weight loss treatment could reduce the need for treatment of each disease by addressing the underlying pathophysiological changes and obesity-related disease.” Sources: American Society of Nephrology, Archives of Neurology, The Lancet

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View from the waiting room by Steve Devrell

World cruise - health check

ELL- I’M BACK SAFELY! 33,000 miles, 32 ports, 26 countries, two equator crossings, five continents, three oceans and 25 different time zones! In fact like most of the 14 million people who will cruise this year, my experience was trouble free. Next year I will join 15 million ‘cruisers’, this time on a more modest excursion around the Caribbean. I must say that I loved virtually every minute of the 82 days, although we did have our moments of high drama. We sailed through a Force 12.1 hurricane in the North Atlantic; we were pursued by pirates in the Arabian Sea until the pirate boat was intercepted by a Royal Naval warship. We narrowly escaped the New Zealand earthquake, missed the Brisbane floods by two weeks, were escorted everywhere by armed guards in Mexico and had to abandon a visit to the

Many passengers were reluctant to visit the medical centre because of the blanket £80 charge for just breathing the same air as the doctor.

Pyramids for security reasons. It was my first ever cruise and the first time I had slept at sea. Nothing like diving in at the deep end! But it was, without any shadow of a doubt, the experience of a lifetime. Some of the health issues and concerns that I highlighted in my pre-cruise article did not really materialise. The predicted seven deaths on board was actually only one, although on the following cruise (a seventeen day trip around the Eastern Mediterranean), five deaths were reported. The ship’s medical centre that included two Intensive care beds dealt with 95% of all reported health problems. The remaining 5% was dealt with by a line of ambulances that seemed to meet the ship at every port where a visit to a land hospital was considered necessary. We had one at-sea transfer to an ambulance launch off the coast of Northern Spain and one rather frantic request for donors

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of a certain blood group. Many passengers were reluctant to visit the medical centre because of the blanket £80 charge for just breathing the same air as the doctor. Instead, many ailments were generally treated by visiting a local pharmacy, where their powers for prescribing appeared far greater than those afforded to pharmacists in the U.K. Personally, I suffered no illness at all whilst I was on board, but I think I was in the minority. Of the six people we ‘grouped’ with on board, I was the only one who didn’t experience some kind of problem ranging from head colds to chest infections. This was perhaps no surprise as the age group of passengers were ,generally speaking, in the late 60s or 70s. Indeed, waiting to check-in at Southampton was very much like joining a long queue on pension day. One unfortunate young couple had hopelessly misjudged the age group on board and booked the World Cruise for their honeymoon. It may have been a long 82 days for them! I did finally step off the ship in Southampton feeling both fulfilled and relieved that we had survived the cruise unscathed. But I couldn’t help feeling troubled by the way cruise companies appear to promote unhealthy lifestyles in order to fulfil the demands of their client base. It really was quite rare to find someone who was not at least noticeably overweight. Many and I mean MANY of my fellow passengers were, to put it kindly, clinically obese. Mobility issues were a concern for many on board the ship. It is hard to generalise or even be precise on such matters, but it was fairly obvious that many of these mobility problems were due to obesity rather than any natural causes. It is easy to see the appeal of cruising for the less mobile. It allows for a very sedentary existence if that is your choice. Indeed many passengers decided not to get off the ship at all and spent their port experiences looking over the railings. Although one can see the merits of making travel easy for the less mobile, should cruise companies actually encourage this inactive existence? I was somewhat troubled by this open invitation to gluttony. Food was available on board 24 hours a day and eating and drinking in excess was positively encouraged. A typical day for many passengers would involve Breakfast from 7am – 11am. Then an hour snack period took you through to lunch which was from noon to 3pm. Afternoon tea was from 4pm - 5.30pm. A six or seven

course meal was available from 6.30pm – 10pm and then snacks were available from midnight through to 6am. In addition there was a free 24 hour cabin service, a cake shop, a sweet shop and eleven bars that stayed open as long as there was passenger who wanted a drink. One of the resident comedians on board remarked ‘I will try to get through my act quickly, because I know some of you haven’t eaten for 45 minutes.’ Many a true word.... The ship paid lip service to healthy living by providing a handful of ‘well-being’ seminars, but by far the most numerous and certainly the most popular were talks on food and drink. I remember innocently trying to return to my cabin when I was accused of pushing into a queue, the queue led to a chocolate making demonstration and tasting session. There were also numerous and popular cookery demonstrations and wine tasting events. Ironically, a talk by a faith healer attracted more people than a talk on preventing high cholesterol. The food on board was excellent, but it did by necessity contain many preservatives and the fruit counter was always the least busy.

wash his hands after using the toilet. Coughing without covering their mouths and waving dirty linen handkerchiefs became quite irritating. Indeed coughing became an epidemic on board and I am sure there was a breakfast competition to see who could cough the loudest. I am certain many of the people on cruise ships come from that generation when personal hygiene procedures were not as rigorous as they are today. Younger generations seem to have been brought to automatically follow basic hygiene measures. Sadly, my generation and older clearly have not. It needs more than polite reminders in the ship’s magazine to ensure these basic procedures are carried out.

The ship paid lip service to healthy living by providing a handful of ‘well-being’ seminars, but by far the most numerous and certainly the most popular were talks on food and drink.

By adopting a great deal of will power, I put on just seven pounds during the cruise (which I have now thankfully lost). Others I spoke to on board expected to put on between two and three stones during the cruise and the ship was very careful not to make weighing scales available to its passengers. It would be easy to blame cruise companies for helping to encourage an unhealthy lifestyle and there is much more they could do to redress this imbalance. Encouraging people to take exercise would be the first and most obvious example. I often noted that perfectly fit people would take the lift to the next floor (sorry deck) rather than walk down 16 steps. The very pleasant promenade deck which had a circuit of a third of a mile in length was often empty. The gym, which was largely unsupervised, was only used by a handful of people, and some of these only used the exercise bikes for somewhere to sit and chat. The major health risk that I encountered however was no fault of the ship and its crew. The public areas were meticulously clean and automatic hand gel dispensers were available all over the ship. The problem was that many of the passengers deliberately avoided these hand cleansing stations, and I observed many a ‘gentleman ‘who didn’t

I appreciate that cruise ship companies are in a difficult position when it comes to pleasing its passengers. Many were clearly on board for a gastronomic experience, others were happy just to laze around on deck like an advert for ‘Land of Leather.’ But cruise companies and health organisations have a captive audience and the experience could be used to monitor people’s health and devise dietary and exercise programmes that would be of benefit. Why not include free health checks on board, or include programmes on exercise and healthy eating. At the moment not enough is done to educate people in promoting a healthy lifestyle. This may involve cruise companies redefining their image slightly. But it is possible to make cruising a healthy option and not a potential death sentence. Sometimes we should be brave enough to give people what they need instead of what they want! 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 3 • J U N E / J U LY 2 0 1 1

Tell me Nathan, how does FOSTAIR

Now licensed for use with AeroChamber Plus

feel? In between number-crunching and biscuit-dunking, FOSTAIR is there for his asthma.

It delivers twice as much medication to the lungs as standard metered-dose inhalers.1,2 A third of the extra-fine particles reach the small airways,1 enabling uniform treatment of inflammation and bronchoconstriction throughout the lung.3,4 So by helping patients get control of their asthma,5 they can get on with the serious business of really living.

FOSTAIR® (beclometasone dipropionate and formoterol fumarate dihydrate) pressurised inhalation solution Prescribing Information (Refer to Summary of Product Characteristics before prescribing) Presentations: Pressurised inhalation solution containing 100 micrograms of beclometasone dipropionate and 6 micrograms of formoterol fumarate dihydrate per actuation. Indications: Regular treatment of asthma where use of a combination product (inhaled corticosteroid and long-acting beta2-agonist) is appropriate: patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled short-acting beta2 agonist; or patients already adequately controlled on both inhaled corticosteroids and long-acting beta2-agonists. Not appropriate for treatment of acute asthma attacks. Dosage and Administration: For inhalation use only. Fostair is not intended for the initial management of asthma. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of beta2-agonists and/or corticosteroids by individual inhalers should be prescribed. Adults: one or two inhalations twice daily, maximum four inhalations daily. Not recommended for patients under 18 years. Beclometasone dipropionate in Fostair is characterised by an extra-fine particle size distribution which results in a more potent effect than formulations of beclometasone dipropionate with a non extra-fine particle size distribution (100 micrograms of beclometasone dipropionate extra-fine in Fostair are equivalent to 250 micrograms of beclometasone dipropionate in a non extra-fine formulation). Therefore the total daily dose of beclometasone dipropionate administered in Fostair should be lower than the total daily dose of beclometasone dipropionate administered in a non-extra-fine beclometasone dipropionate formulation. Fostair may be used with the AeroChamber Plus™ spacer device. Patients should be advised in the proper use and care of their inhaler and spacer. Contraindications: Hypersensitivity to any of the components. Precautions: Cardiovascular disorders including cardiac arrhythmias, thyrotoxicosis, diabetes mellitus, phaeochromocytoma, untreated hypokalaemia, pulmonary infections (tuberculosis, fungal or viral). Fostair should not be used as the first treatment for asthma, should not be initiated during an exacerbation, or during significantly worsening or acutely deteriorating asthma, and should not be stopped abruptly. If patients find the treatment ineffective medical attention must be sought. Systemic

effects of inhaled corticosteroids may occur, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhaled than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma. Titrate to the lowest dose at which effective control of asthma is maintained to minimise systemic effects. Special care is needed in transferring patients from oral steroids. Fostair contains a small amount of ethanol (approximately 7mg per actuation); at normal doses the amount of ethanol is negligible and does not pose a risk to patients. Patients should rinse mouth after inhalation to minimise risk of oropharyngeal candida infection. Drug interactions: Beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes without involvement of the cytochrome p450 system. Avoid beta-blockers (including eye drops). Caution is required when theophylline or other beta-adrenergic drugs are prescribed concomitantly with formoterol. Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, MAOIs and TCAs can prolong the QTc interval and increase the risk of ventricular arrhythmias. In addition, L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance. Concomitant administration with MAOIs, including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertension. Risk of arrhythmias in patients receiving anaesthesia with halogenated hydrocarbons. Theoretical potential for interaction in sensitive patients taking disulfiram or metronidazole. Pregnancy and Lactation: No experience. Balance risks with benefits. Side effects: Common: pharyngitis, headache, dysphonia. Uncommon: influenza, oral fungal infection, pharyngeal and oesophageal candidiasis, vaginal candidiasis, gastroenteritis, sinusitis, granulocytopenia, dermatitis allergic, hypokalaemia, hyperglycaemia, restlessness, tremor, dizziness, otosalpingitis, cardiac arrhythmias, hyperaemia, flushing, rhinitis, cough, productive cough, throat irritation, asthmatic crisis, pruritus, rash, hyperhidrosis, diarrhoea, dry mouth, dyspepsia, dysphagia, burning sensation of the lips, nausea, dysgeusia, muscle spasms, myalgia, C-reactive protein increased, platelet count increased, free fatty acids increased, blood insulin increased, blood ketone body increased. Rare: ventricular extrasystoles, angina pectoris, paradoxical bronchospasm, urticaria, angioneurotic oedema, nephritis, blood pressure increased, blood pressure decreased. Very rare: thrombocytopenia, hypersensitivity reactions, adrenal suppression, abnormal behaviour, sleep disorder, hallucination, glaucoma,

cataract, atrial fibrillation, dyspnoea, exacerbation of asthma, growth retardation in children and adolescents, peripheral oedema, bone density decreased. Legal Category: POM Packs and Prices: Fostair 100/6 (PL08829/0156) £29.32. Each inhaler contains 120 actuations. Full prescribing information is available from the Marketing Authorisation Holder: Chiesi Limited, Cheadle Royal Business Park, Highfield, Cheadle, SK8 3GY. Date of preparation: January 2011. REFERENCES 1. De Backer W, Devolder A, Poli G et al. Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic and COPD patients. J Aerosol Med Pulm Drug Deliv 2010; 23(3): 137-148. 2. Selroos O, Pietinalho A, Riska H. Delivery devices for inhaled asthma medication. Clin Immunother 1996; 6: 273-299. 3. Fabbri LM, Nicolini G, Olivieri D et al. Inhaled beclometasone dipropionate/ formoterol extra-fine fixed combination in the treatment of asthma: evidence and future perspectives. Expert Opin Pharmacother 2008; 9: 479-490. 4. Tulic MK, Hamid Q. New insights into the pathophysiology of the small airways in asthma. Clin Chest Med 2006; 27: 41-52. 5. Huchon G, Magnussen H, Chuchalin A et al. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med 2009; 103: 41-49. AeroChamber PlusTM is a licensed trademark of Trudell Medical International. Date of preparation: JANUARY 2011 | Job code: CHFOS20110090

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to Chiesi Limited (address as above). Tel: 0161 488 5555.