Evidentia Nov Dec Issue 2010

Volume 4 Issue 6 November/December 2010 ISSN 1753-464X

Conference reports from: Barcelona, Berlin, Geneva, Manchester and Stockholm

LET’S THINK

IF ONE OF US CAN COME UP WITH AN IDEA TO HELP OUR PATIENTS, WHAT COULD ALL OF US COME UP WITH?

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Bringing clinical evidence to practice in primary and secondary care

CONTENTS 4

Guest Editorial - The difficult asthma clinic by Dr. Gareth Riddell & Dr. Liam Heaney

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Heart patients with anxiety disorder experience more cardiovascular events Reports from the European Federation of Neurological Societies meeting, Geneva

COVER STORY Volume 4 Issue 6 November/December 2010 ISSN 1753-464X

10 Unique data on the long-term use of inhaled corticosteroid budesonide Reporting from the European Respiratory Society Annual Congress, Barcelona

14 Increased risk of MI in winter sports vacations Reporting from the European Society of Cardiology meeting, Stockholm

18 Diabetic neuropathy: The winding road from early detection to timely prevention Reporting from the European Association for the Study of Diabetes meeting, Stockholm Conference reports from: Barcelona, Berlin, Geneva, Manchester and Stockholm

22 Acne and increase risk of suicide: isotretinoin may not be to blame Reporting from the British Association of Dermatologists annual meeting, Manchester

24 Nicotine dependence and pharmacological interventions: a review

14 MI risk for unprepared winter sports tourists

Smoking cessation report

26 Nurses reduce risk of recurrent complications: results from the RESPONSE trial - Cardiology report

27 EMA Highlights - Emerging uses of EMA approved drugs 28 The BIG FOUR - Reporting from some of the latest journal articles 30 World Health Matters - Medical news from around the world 32 FDA Highlights - Emerging uses of FDA-approved drugs 34 View from The Waiting Room - No country for old men 23 4

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Guest Editorial Dr. Gareth Riddell & Dr. Liam Heaney, Regional Respiratory Centre, Belfast City Hospital

The difficult asthma clinic

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asthma clinic is to confirm the diagnosis. This may be at the initial assessment based on a typical history, along with supporting evidence of reversible airflow obstruction. However, often lung function is normal and there may be atypical features. In these cases, review of the original diagnosis and supportive evidence is required. The diagnosis is more likely if there is a history of hayfever, eczema or childhood wheeze, or a strong family history of these.

Previous hospital admissions with hypoxia and wheeze, and high inflation pressures if intubated, are other elements of the history which can help to support the diagnosis.

Factors supporting a diagnosis of asthma such as atopy can be checked for with skin prick and RAST testing, and checking the IgE and eosinophil count can be useful too.

A chest X-ray, lung volumes and diffusion capacity can assist with diagnosis and help exclude other conditions. Peak flow charts are less used now to show variability in lung function due to problems with reliability.4 Often there can be coexisting disease, such as bronchiectasis, and some of the patients do not have asthma at all, but have another condition leading to their symptoms such as vocal cord dysfunction or dysfunctional breathing. These other diagnoses can be difficult to clarify on A chest X-ray, lung volumes and diffusion capacity can assist with history alone and often require further testing. diagnosis and help exclude other conditions.

here is no gold-standard definition of asthma, but all definitions refer to symptoms such as cough, wheeze and breathlessness and their variability over time. The diagnosis of asthma is normally easily made and the condition often responds to inhaled therapy.

However, 5 - 10% of asthmatics do not respond to prescription of maximal doses of preventative treatment and are said to have difficult asthma.1 Since some patients with difficult to control asthma may not have asthma at all, or have other conditions contributing to their symptoms,2,3 bringing them to a difficult asthma clinic gives an opportunity to adopt a systematic multi-disciplinary team approach to the diagnosis and management of this condition.

The most important initial step at the difficult

Contributors: Maria Dalby, Steve Devrell, Dr. Julie Eastgate, Gary Finnegan, Dr. Liam Heaney, Peter Mas-Mollinedo, Claire Payne, Dr. Gareth Riddell, Bruce Sylvester, Samuel Peters.

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

Additional investigations such as a high resolution CT, video fluoroscopy when symptomatic or a cardiopulmonary exercise test can be helpful in identifying conditions which cause symptoms similar to asthma.

Prominent rhino-sinusitis symptoms often co-exist with asthma and require evaluation and treatment. There is some evidence to suggest that control of the nasal symptoms improves asthma control 5 and therefore nasal steroids and a referral to an ENT surgeon for possible surgery is often required.

In those with a confirmed diagnosis of asthma, difficult to control asthma is often due to poor or non-adherence with medications, rather than true refractory asthma.6 Patients will often state that they are taking their medications, but actually avoid them for various reasons. For example, they may not use their inhaled steroid whenever they feel well, and they may not take their oral steroids due to concern about side effects. Even if they are taking their inhalers, this is often not at the dose or timings that have been prescribed and inhaler technique may be sub-optimal.

Identifying these patients can be difficult, but checking records of prescriptions collected and measuring serum theophylline, and serum prednisolone with cortisol levels if appropriate can provide the objective evidence required.

A raised fractional exhaled nitric oxide (FeNO) level may reflect underlying airways inflammation and if very elevated (>100 ppb) should raise a suspicion of non-adherence. If non-adherence is still suspected, and evidence is still required, an injection of intramuscular steroid e.g. Kenalog can lead to a dramatic improvement of symptoms, which confirms the disease is steroid responsive and would suggest poor control due to steroid avoidance. When confronted with objective evidence of non-

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ICR-UK Limited, PO Box 448, West Byfleet, Surrey KT14 9AU Tel: 0845 094 1699 Fax: 0845 094 1690 © 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 D i r e c t M a r k e t i n g 0 1 2 8 4 7 1 8 9 0 0

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European Federation of Neurological Societies adherence, patients will often admit this is the case and this allows for a more informed discussion and a management plan to be agreed with the patient, taking into account their concerns. Even if patients are taking their medication, incorrect use of inhalers is common, and therefore it is imperative to check inhaler technique whilst at the clinic.

Depression and anxiety are extremely common in the difficult asthma population,7 however, robust evidence that treating these improves asthma control is lacking.

Psychological problems can be identified using validated questionnaires and asking about symptoms of depression can allow treatment of the problem and in our experience, often leads to an improvement of the patient’s condition.

For patients on Step 5 of BTS asthma management guidelines, there are other pharmacological options available. Steroid sparing medications, such as methotrexate or ciclosporin can sometimes be used. If patients fulfil the criteria of atopy and severity they may be suitable for a trial of omalizumab, which can reduce or eliminate their steroid use. Other therapeutic options may become availale in the near future for patients with severe disease e.g. bronchial thermoplasty, mepolizumab (anti-IL5) and anti IL-13 treatments.

Diagnosis and management of the refractory asthmatic requires a team approach involving the asthma nurses and doctors, and when appropriate the ENT specialists, clinical psychologists, speech therapists and pharmacists. Whilst there is still no cure for asthma, optimal management of this condition can reduce the associated morbidity and mortality.

References: 1. British Guideline on the Management of Asthma. British Thoracic Society & Scottish Intercollegiate Guidelines Network. Thorax 2008 May; 63(Suppl 4: iv1-121) 2 Heaney LG, Conway E, Kelly C, Johnston BT, English C, Stevenson M, Gamble J. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol.

Thorax 2003; 58(7): 561-6 3. Robinson DS, Campbell DA, Durham SR, Pfeffer J, Barnes PJ, Chung KF. Systematic assessment of difficultto-treat asthma. Eur Respir J 2003; 22(3): 478-83 4. Reddel H, Jenkins C, Woolcock A. Diurnal variability - time to change asthma guidelines? BMJ 1999; 319: 45-47 5. Allergic rhinitis and its impact on asthma. ARIA workshop report. J Allergy Clin Immunol 2001; 108(Suppl 5): S147-S334 6. Gamble J, Stevenson M, McClean E, Heaney L. The Prevalence of Nonadherence in Difficult Asthma. Am J Respir Crit Care Med 2009; 180: 817-822 7. Heaney LG, Conway E, Kelly C, Gamble J. Prevalence of psychiatric morbidity in a difficult asthma population: relationship to asthma outcome. Respir Med 2005; 99(9): 1152-9

Reports from the EFNS meeting, Geneva

Heart patients with anxiety disorder experience more cardiovascular events

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mong patients with heart disease, anxiety disorders appear to be associated with a higher risk of stroke, heart attack, heart failure and death, according to a report in a recent issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

As many as 24% to 31% of patients with heart disease also have symptoms of anxiety, according to background information in the article. "Compared with the extensive literature on depression in patients with coronary heart disease, relatively few studies have examined the role of anxiety," the authors write. "Several studies have found that anxiety symptoms are predictive of disability, increased physical symptoms and worse functional status and quality of life in patients with coronary heart disease. However, studies examining anxiety as a risk factor for future coronary heart disease have yielded conflicting results."

Elisabeth J. Martens, Ph.D., of Tilburg University, Tilburg, the Netherlands, and colleagues assessed 1,015 outpatients with stable coronary heart disease. The baseline examination consisted of interviews, blood and urine sample testing, exercise testing and electrocardiography. The presence of generalised anxiety disorder and of depressive disorder was determined using the computerised version of the Diagnostic Interview Schedule.

After an average follow-up time of 5.6 years, a total of 371 cardiovascular events occurred.

After adjusting for age, the yearly rate of cardiovascular events was 9.6% in the 106 participants with general anxiety disorder and 6.6% in the 909 participants without. After further adjustments for potentially confounding variables - including sex, cooccurring conditions, heart disease severity and medication use - generalised anxiety disorder was associated with a 74% increased risk of cardiovascular events.

"This leaves the question of why generalised anxiety disorder is associated with adverse outcomes in patients with coronary heart EVIDENTIA •

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disease," the authors write. Anxiety may be associated with surges in catecholamines, "fight or flight" hormones that may be related to heart risks, they suggest. Alternatively, patients with anxiety may be more likely to seek care when they have symptoms and therefore be more likely to receive a diagnosis of stroke or heart attack, although this would not explain the increased risk of death. It is also possible that a common underlying factor predisposes individuals to both anxiety and heart events.

‘

Several studies have found that anxiety symptoms are predictive of disability, increased physical symptoms and worse functional status and quality of life in patients with coronary heart disease.

’

"These findings have implications for clinical practice and research," they conclude.

"Generalised anxiety disorder may be considered a prognostic factor in patients with coronary heart disease and could be used in risk stratification. Evaluation and treatment of anxiety may also be considered as part of the comprehensive management of patients with coronary heart disease. Research programmes designed to advance our understanding of the impact of generalised anxiety disorders on medical prognosis and biobehavioral mechanisms that link anxiety to mortality in the context of coronary heart disease are needed to develop evidence-based approaches to improving patient care."

Reference: Arch Gen Psychiatry 2010; 67[7]: 750-758 ISSUE 6 •

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European Federation of Neurological Societies - by Peter Mas-Mollinedo Reports from the EFNS meeting, Geneva

People with anxiety disorder, ‘less able to regulate response to negative emotions’

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eople with generalised anxiety disorder, or GAD, have abnormalities in the way their brain unconsciously controls emotions. That's the conclusion of a new Stanford University School of Medicine study, and the study authors say the findings could open up new avenues for treatments and change our understanding of how emotion is regulated in everyday life.

The work is published online in the American Journal of Psychiatry.

According to the National Institute of Mental Health, 18% of Americans have an anxiety disorder. GAD in particular is marked by extreme feelings of fear and uncertainty; people with the disorder live in a state of non-stop worry and often struggle getting through their daily lives.

"Patients experience anxiety and worry and respond excessively to emotionally negative stimuli, but it's never been clear really why," said Amit Etkin, MD, PhD, acting assistant professor of psychiatry and behavioural sciences and first author of the study.

Etkin said clinical data have suggested that adult GAD patients initially register negative stimuli in a largely normal way, but have deficits in how they then control negative emotions. He and his colleagues conducted their research to better understand these potential abnormalities and to shed light on two theories dating back to Sigmund Freud: that most emotion regulation is done unconsciously, and that a disturbance in unconscious emotion regulation leads to psychiatric symptoms.

For the study, Etkin recruited 17 people with GAD and 24 healthy participants and used functional magnetic resonance imaging and a behavioural marker to compare what happened when the two groups performed an emotionbased task. The task involved viewing images of happy or fearful faces, overlaid with the words "fear" or "happy," and using a button box to identify the expression of each face. Not all the words matched up - some happy faces featured the word "fear," and vice versa - which created an emotional conflict for participants.

The authors' previous work involving the

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task has shown that it takes study subjects longer to identify the correct expression when the expression and word contradict one another. But the slowdown in reaction time is lessened if the previous image was also incongruent, demonstrating that an emotion regulatory process kicked in to help the brain react faster to the conflicting emotional information. "We can see through the reaction-time effect that people are adapting their emotional processing" from image to image, Etkin explained.

‘

He said the differences

between the two groups

were striking. By looking at reaction times alone, we could classify who

was a patient and

’

who was a control.

Amit Etkin

In the current study, Etkin and his colleagues found that both healthy participants and GAD patients were able to identify the expressions.

Healthy participants, as was expected, reacted more quickly to incongruent images when the previous image was also incongruent. When later asked if they were aware of any pattern that might have helped or hindered their performance, the volunteers said they were not; Etkin said this demonstrated that this process was carried out unconsciously.

However, the researchers found that in the GAD patients, the reaction-time effect seen in healthy patients was absent - and in the most anxious patients, reaction time actually worsened when there were two incongruent images in a row. "GAD patients had decreased ability to use emotional content from previous stimuli to help them with the task," said Etkin.

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He said the differences between the two groups were striking. "By looking at reaction times alone, we could classify who was a patient and who was a control," he said, adding that this represented the first solid demonstration that a psychiatric population has a deficit in a form of unconscious emotion regulation.

Earlier work from Etkin and colleagues had shown that when healthy subjects encountered the emotional conflict during this task, the pregenual anterior cingulate, a part of the brain's prefrontal cortex, was activated. That part of the brain then inhibited the amygdala, which acts to dampen or regulate negative emotion.

During this study, the brains of health participants reacted as expected. But for patients with GAD, the pregenual anterior cingulate failed to light up and to inhibit the amygdala, showing something went awry with this circuit. This has never been shown before, Etkin noted.

Understanding that the prefrontal cortex is an important site of abnormality could potentially lead to advances in more accurate diagnosis and effective treatment. By targeting this region more directly, clinicians might be able to improve regulation function in GAD patients. Etkin also suspects that a faulty pregenual cingulate-amygdala circuit during unconscious emotion regulation is involved in other psychiatric disorders, such as post-traumatic stress disorder, so the work could lead to a better understanding of those conditions.

Senior study author Alan Schatzberg, MD, the Kenneth T. Norris, Jr. Professor and chair of psychiatry and behavioural sciences, noted that the findings bring new insight into the biology of psychopathology, as well as potentially the mechanisms underlying the response to psychotherapy. They could, he said, provide a new way also to gauge the efficacy of therapy.

Etkin said he'll continue his investigations in this area, and use these findings to identify brain signatures that differ among psychiatric disorders, as well as to track the effects of psychotherapy.

Contact: Michelle Brandt mbrandt@stanford.edu

European Federation of Neurological Societies - by Peter Mas-Mollinedo Reports from the EFNS meeting, Geneva

iPhone Images: good enough for medical use?

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ike the rest of society, medicine increasingly relies on digital systems and mobile devices to manage work flow and enhance communications.

Ophthalmologists routinely evaluate internet-transmitted images of patients' eyes as part of diagnosis and treatment.

Usually images are viewed at computer workstations with standard display screens.

University of Pittsburg School of Medicine researchers wondered whether handheld devices like the iPhone would work equally well.

In the study, eye doctors from the University of Pittsburg Eye Center evaluated three aspects of diabetic retinopathy, a potentially blinding disease that affects many people with diabetes, by reviewing both the standard computer monitor and iPhone images for 55 patients (110 eyes). The doctors then made recommendations for follow-up treatment.

"We found high consistency – more than 85% agreement – between evaluations based on the standard computer monitor and on the iPhone for all image sections tested," said Dr. Michael J. Pokabla. "There were no significant differences between evaluations and recommendations using the two systems, and the doctors rated the iPhone images as excellent. We conclude that mobile devices like the iPhone can be used to evaluate ophthalmic images," he added.

When no ophthalmologist is available on site, some emergency rooms (ERs) in

remote medical centres in rural Australia now use videoconferencing to receive diagnosis and treatment advice for their eye injury and ophthalmic illness patients.

A telecommunication link at a major metropolitan teaching eye hospital, the Royal Victorian Eye and Ear Hospital (RVEEH), is connected with four ERs that serve large regions of rural Australia. Dr. Christolyn Raj and her team studied the effectiveness of this approach by reviewing the initial six months of RVEEH video conference interactions with the regional ERs. Diagnoses were altered in approximately 60% of cases and management plans were changed in about 70% of cases following video conference consultations, study results show.

The average consultation time was ten minutes.

"Video conferencing is a sustainable, effective way of providing prompt eye management advice to rural emergency doctors," Dr. Raj said.

"Although it can never replace face to face clinical care, it is a useful tool to have at one's fingertips and its use will undoubtedly increase in coming years," she added.

The blood pressure-glaucoma connection in people with migraine

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ata on glaucoma risk in people with migraine and on innovative uses of mobile, digital technology were featured at the 2010 American Academy of Ophthalmology (AAO) - Middle East-Africa Council of Ophthalmology (MEACO) Joint Meeting. The AAO-MEACO meeting is the largest, most comprehensive ophthalmic education conference in the world.

Yury S Astakhov, MD, PhD, of Pavlov Medical University, St. Petersburg, Russian Federation, studied how day- and at night-time blood pressure levels may be related to the development of glaucoma in people with

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migraine. Understanding such effects is important for doctors in determining how to treat patients with multiple diseases.

Migraine is a known risk factor for openangle glaucoma, a disease that can cause blindness due to damage to the optic nerve.

The association between the two is stronger for people with "normal tension" glaucoma (NTG), in which the pressure within the eye is normal but optic nerve damage occurs nonetheless. It is also known that glaucoma patients who have low blood pressure at night are more likely to develop visual field loss (reduction of the full range of vision, which occurs first in the

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peripheral vision).

Dr. Astakhov's team compared day- and night-time systolic and diastolic blood pressures in 12 patients who had migraine and glaucoma (8 with NTG) against 16 patients with migraine but no glaucoma. The only significant difference between the groups was in night time diastolic pressure: migraine patients with glaucoma had excessive decreases – more than 20% – in their diastolic pressure levels.

"We conclude that low diastolic blood pressure at night is a possible risk factor for glaucoma in patients with migraine," Dr. Astakhov said.

Help put migraine behind her

A long lasting triptan for sustained migraine relief

Migard 2.5mg film-coated tablets (frovatriptan) Abbreviated Prescribing information Please consult the Summary of Product Characteristics (SPC) for full prescribing information.

Presentation: Film-coated tablets containing 2.5mg frovatriptan.

Contains lactose. Use: Acute treatment of the headache phase of migraine attacks with or without aura. Dosage: Oral administration. Adults: 2.5mg. Max 5mg in 24 hours. Not recommended for use in children, adolescents, patients over 65 and patients with severe hepatic impairment. Contraindications: Hypersensitivity, history of myocardial infarction, ischaemic heart disease, coronary vasospasm, peripheral vascular disease, signs of ischaemic heart disease. Severe, moderately severe or uncontrolled hypertension. Previous cerebrovascular accident or transient ischaemic attack, severe hepatic impairment, concomitant administration with ergotamine, ergotamine derivatives or other 5-HT1 receptor agonists.

Warnings and Precautions: Establish clear diagnosis. Do not use for hemiplegic, basilar or ophthalmoplegic migraine. In common with other 5-HT1 agonists, care with coronary artery disease, heavy smokers, users of nicotine substitution therapy.

Specific attention to post-menopausal women and men over 40 years of age with these risk factors. Very rare cases of serious cardiac events in patients with no underlying cardiovascular disease. Allow 24 hours between doses of frovatriptan and ergotamine-type medications. Overdose can lead to increased side-effects. Prolonged use of painkillers for headaches can make them worse. Contains lactose, therefore, do not give to patients with galactose intolerance, Lapp lactase deficiency or

glucose-galactose malabsorption. Concomitant use with St. John’s wort, pregnancy and lactation. Interactions: Ergotamine and ergotamine derivatives, monoamine oxidase inhibitors.

Please consult the SPC for other interactions. Side-effects: Common (1-10%): dizziness, paraesthesia, headache, somnolence, dysaesthesia, hypoaesthesia, visual disturbance, flushing, throat tightness, nausea, dry-mouth, dyspepsia, abdominal pain, hydrohidrosis, fatigue, chest discomfort.

Uncommon (0.1-1%): Dehydration, anxiety, insomnia, confusional state, nervousness, agitation, depression, depersonalisation, dysgeusia, tremor, disturbance in attention, lethargy, hyperaesthesia, sedation, vertigo, involuntary muscle contractions, eye pain, eye irritation, photophobia, tinnitus, ear pain, palpitations, tachycardia, peripheral coldness, hypertension, rhinitis, sinusitis, pharyngolaryngeal pain, diarrhoea, dysphagia, flatulence, stomach discomfort, abdominal distension, pruritus, musculoskeletal stiffness, musculoskeletal pain, pain in the extremity, back pain, arthralgia, pollakiuria, polyuria, chest pain, feeling hot, temperature intolerance, pain, asthaenia, thirst, sluggishness, energy increased, malaise. Rare (0.1-0.01%): Lymphadenopathy, hypoglycaemia, abnormal dreams, personality disorder, amnesia, hypertonia, hypotonia, hyporeflexia, movement disorder, night blindness, ear discomfort, ear disorder, ear pruritus, hyperacusis, bradycardia, epistaxis, hiccups, hyperventilation, respiratory disorder, throat irritation, constipation, eructation, gastroesophageal reflux disease, irritable bowel syndrome, lip blister, lip pain, oesophageal spasm, oral mucosal blistering, peptic ulcer, salivary gland pain,

stomatitis, toothache, erythema, piloerection, purpura, urticaria, nocturia, renal pain, breast tenderness, pyrexia, blood bilirubin increased, blood calcium decreased, urine analysis abnormal.

Unknown frequency: hypersensitivity reactions including cutaneous disorders and anaphylaxis. Package quantities and price: 6 tablets: £16.67. Legal category: POM. Marketing Authorisation Number: PL 16239/0017. Marketing Authorisation holder: Menarini International Operations Luxembourg S.A. Marketed by: A. Menarini Pharma U.K. S.R.L. Further information is available on request to A. Menarini Pharma U.K. S.R.L. Menarini House, Mercury Park, Wycombe Lane, Wooburn Green, Buckinghamshire, HP10 0HH, UK or may be found in the SPC. Last updated: October 2008

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to A.Menarini Pharma U.K. S.R.L. Phone no. 0800 085 8678 Date of preparation: September 2010 3286/MIG/SEP/2010/HRK Migard® is a registered trademark of A. Menarini Pharma U.K. S.R.L.

European Respiratory Society - by Maria Dalby Reporting from the ERS Annual Congress, Barcelona

Unique data on the long-term use of inhaled corticosteroid budesonide Søren Pedersen, Pediatric Research Unit, Kolding Hospital, Denmark

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longitudinal study of a group of children with asthma attending a regional hospital in Western Denmark has provided unique data on the long-term use of inhaled corticosteroid budesonide. The study was initiated in 1986

by Professor Søren Pedersen and Dr. Lone Agertoft, and has since provided a wealth of data showing that budesonide has a very favourable safety profile in children. One of the most important findings in this study to date is the data published in 2000, that children treated with budesonide at therapeutic doses for a mean of 9 years achieved normal adult height.1 In the most recent analysis from this study, which was presented by Professor Pedersen at the ERS 2010 Annual Congress, children receiving budesonide for a mean of 15.7 years (range 2.4–32 years) at a mean daily dose of 385 micrograms (range 50 – 1,220) showed no increase in intraocular pressure (IOP) or in the incidence of posterior subcapsular cataracts (PSCs). This data is unique since most published studies that have assessed the development of

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ocular adverse effects associated with oral or inhaled corticosteroids have been crosssectional, with little or no information available on the dose used.

The study population included 300 asthmatic children treated with budesonide since 1986.

The budesonide dose given was reviewed regularly and adjusted as required to maintain asthma control. Once the patients reached adult age, they and their non-asthmatic siblings were invited to undergo a slit-lamp examination with retroillumination images and assessment of IOP by a certified ophthalmologist. PSCs were graded using the Lens Opacities Classification System III. The present analysis comprised 147 patients and 53 healthy siblings who were seen during 2009. Their mean ages at the time of the visit were 26.4 and 27.5 years, respectively. The mean accumulated budesonide dose was 2,258mg (range 244–8,760mg). Overall, the mean IOP was similar in the patient group (13.8mmHg [95% CI 13.3, 14.3]) and in the healthy controls group (14.4mmHg [95% CI 14.0, 14.8]). One person in the healthy controls

• • • • • • •

group (1.9%) and 5 patients (3.4%) had an IOP >21mmHg (p=NS). No correlation was found between IOP and the duration of treatment or the accumulated or current dose of budesonide.

Visual acuity was identical in the two groups at 1.04 in both groups on both eyes.

Two PSCs were found in the healthy controls group whereas none of the patients were found to have PSC. Professor Pedersen pointed out that to demonstrate a statistically significant (5% level) increase in the risk of PSC with budesonide, a minimum of 19 PSCs would have been required in the budesonide group. Professor Pedersen concluded that treatment with inhaled budesonide in children with chronic asthma at a mean daily dose of 385µg for a mean of 15.7 years was not associated with any adverse effects in adulthood on intraocular pressure or the occurrence of posterior subcapsular cataracts, providing a unique safety record for an inhaled corticosteroid.

Reference: 1. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343 (15): 1064-1069

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Biomass smoke is a major cause of COPD worldwide Alejandra Ramirez-Venegas, National Institute of Respiratory Diseases, Mexico City, Mexico

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original research papers and meta-analyses 0.62, 0.92, p=0.005).5 In Mexico, a ne of the most common and between smoking COPD and biomass COPD. most harmful sources of air government-funded intervention programme pollution is also one of the most has been initiated where patsaris (traditionalFigure 1. under-recognised and undertype stoves with flues) have been researched. Although smoke installed in rural homes. Although 2005 - 2010 Smoking Biomass from domestic biomass fuel adherence in this study was reported to Clinical Trial 210 0 stoves constitutes the world's be low (50%), use of the patsari in the In Vitro 8 0 most important source of indoor home was associated with a Editorial 84 2 air pollution, it is only recently significantly lower risk of respiratory Meta-analysis 23 2 that this problem has become the symptoms (relative risk of cough 0.77; Letters 47 0 subject of epidemiological study 95% CI 0.62, 0.95; relative risk of Review 495 7 and larger-scale prevention wheezing 0.29; 95% CI 0.11, 0.77) and Comparative Studies 285 3 efforts. The worst affected are also of non-respiratory symptoms Animals 226 0 women and children in including eye discomfort, headache, Humans 2257 26 developing countries, and lung and back pain.6 In addition, use of the Journal Articles 2400 26 disease is by far the predominant patsari slowed FEV1 decline (31 ml) Randomised morbidity. compared with the open fire use (62 ml) 95 1 controlled trials Dr. Alejandra Ramirez-Venegas over 1 year of follow-up (P = 0.012). leads a team of researchers at the Dr. Ramirez- Venegas concluded her talk Literature search, tobacco smoke and National Institute of Respiratory Diseases in by emphasising the need for further efforts to biomass smoke as a risk factor for COPD. Mexico City. In a talk that formed part of a reduce the burden of biomass smoke exposure plenary symposium focusing on non-smoking and to conduct large-scale multi-national studies presentations of chronic obstructive To date, the key available data set consists of a to uncover the epidemiology and clinical pulmonary disease (COPD), Dr. Ramirezhandful of case control and cross-sectional phenotype of COPD due to biomass fuel smoke.

Venegas presented an overview of the studies, with no population-based longitudinal References: emerging field of airway disease secondary to studies and only one randomised clinical trial. A 1. Pandey MR, Boleij JS, Smith KR, Wafula EM. Indoor biomass smoke. The key to the extent of the recent meta-analysis from the Guangdong region air pollution in developing countries and acute problem is the sheer magnitude of exposure: it in China revealed an overall odds ratio (OR) of respiratory infection in children. Lancet 1989; has been estimated that 50% of the world 2.44 (95% CI, 1.9-3.33) for people exposed to 1(8635): 427-429 2. Bruce N, Perez-Padilla R, Albalak R. Indoor air population use biomass solid fuels for cooking biomass smoke to develop COPD, compared pollution in developing countries: a major and domestic heating; in rural areas the figure with those not exposed to biomass smoke.3 environmental and public health challenge. Bull 1,2 is nearer to 90%. Overall, the World Health Similar results were obtained by a team in World Health Organ 2000; 78(9): 1078-1092 Organisation (WHO) estimates that over 3 Birmingham in the UK, in a systematic review and 3. Hu G, Zhou Y, Tian J, et al. Risk of COPD from billion people worldwide are exposed to meta-analysis which found positive correlations exposure to biomass smoke: a metaanalysis. Chest 2010; 138(1): 20-31 biomass smoke on a regular basis. Exposure is between solid fuel smoke exposure and COPD 4.

Kurmi OP, Semple S, Simkhada P, Smith WC, Ayres expected to continue to increase at least until (OR=2.80, 95% CI 1.85 to 4.0) and chronic JG. COPD and chronic bronchitis risk of indoor air 4 2030. Currently one half of all deaths due to bronchitis (OR=2.32, 95% CI 1.92 to 2.80). pollution from solid fuel: a systematic review and COPD in developing countries are attributable In her presentation, Dr. Ramirez-Venegas meta-analysis. Thorax 2010; 65(3): 221-228 to biomass smoke. stressed that COPD associated with biomass 5. Chapman RS, He X, Blair AE, Lan Q. Improvement in household stoves and risk of chronic obstructive Compared with COPD due to smoking, smoke is easily preventable by comparatively pulmonary disease in Xuanwei, China: retrospective epidemiological data on COPD due to biomass simple measures. In the Xuanwei region in cohort study. BMJ 2005; 331(7524): 1050 smoke is woefully scarce. Despite having been China, adding chimneys to unvented coal stoves 6. Romieu I, Riojas-Rodríguez H, Marrón-Mares AT, et first described at around about the same point resulted in a dramatic reduction in the incidence al. Improved biomass stove intervention in rural in time – around the 1960s – a literature search of COPD (relative risk in men 0.58; 95% CI 0.49, Mexico: impact on the respiratory health of women.

Am J Respir Crit Care Med 2009; 180(7): 649-656 revealed a huge discrepancy in the number of 0.70; p<0.001; relative risk in women 0.75; EVIDENTIA •

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11

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 beta 2-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, pulmonar y 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 ver y 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 inter val 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: July 2010.

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 L M, N icolini G , O livieri D e t a l. I nhaled b eclometasone d ipropionate/ 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: AUGUST 2010 | Job code: CHFOS20100334

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.

TM

European Respiratory Society - by Maria Dalby Reporting from the ERS Annual Congress, Barcelona

COPD and me: development of a patient management plan Ms. Terry Robinson, Harrogate and District NHS Foundation Trust, North Yorkshire, UK

W

hat can a respiratory nurse team do to improve COPD management in a rural health trust the size of a small European country?

Terry Robinson and her colleagues from the North Yorkshire primary care trust (an area which is geographically larger than Belgium) have developed a communications tool, the ‘COPD and Me’ individualised management plan and hand-held record, which promise to be helpful for patients and healthcare professionals to gain a better understanding of COPD and to meet the daily challenges of the condition.

The idea for the 'COPD and Me' tool was born out of the experience within the primary care trust that many patients had a poor understanding of what COPD actually was and what it meant to them, and also the perhaps even more worrying finding that many healthcare professionals within the trust lacked sufficient skills to accurately diagnose and manage COPD. Since COPD at present affects up to 3.8 million people across the UK, these shortcomings resulted in much unnecessary morbidity and mortality, placing a heavy burden on the trust in terms of medical services and frequent hospital admissions.

The full scope of the problem in North Yorkshire was assessed through questionnaires (the Bristol COPD Knowledge Questionnaire1) and focus groups with patients, carers and healthcare professionals. The questionnaire, which was administered to a total of 50 patients with a confirmed diagnosis of COPD, showed evidence of widespread misunderstandings regarding the medications given to COPD patients, exacerbation management and the importance of interventions such as pulmonary rehabilitation.

In her presentation, Terry Robinson mentioned in particular one tragic case where an interview with a patient with severe COPD uncovered significant knowledge gaps and mixed

Yorkshire primary care trust to bring about real messages, and where the patient died shortly change for COPD patients and their families, after admission to hospital. and that the tool could be of great value for The overall aim in the development and healthcare professionals across the UK. implementation of the 'COPD and Me' tool was to co-ordinate the care and management References: efforts and to fulfil the criteria for patient self1. White R, Walker P, Roberts S, et al. Bristol COPD management set out locally within the trust Knowledge Questionnaire (BCKQ): testing what we and nationally by the National Institute for teach patients about COPD. Chron Respir Dis 2006; 3 2 Health and Clinical Excellence (NICE).

(3): 123-131 The finalised tool took the shape of a 2. National Clinical Guideline Centre. (2010) Chronic document containing 6 inserts, providing basic obstructive pulmonary disease: management of information on COPD, details of the individual chronic obstructive pulmonary disease in adults in patient’s normal status (including spirometry primary and secondary care. London: National Clinical results and oxygen levels), medications, Guideline Centre. exacerbation management, goals and objectives, and palliative/supportive care where applicable. The tool has been implemented at hospital admissions (including a followup session at the point of discharge), via COPD reviews at GP surgeries, and also via community nurses on home visits to housebound patients.

In addition, the team has run educational events for healthcare professionals and an education group for patients and carers. Overall, the tool has been well received and patients have reported that it has empowered them to seize control and self-manage this highly challenging condition.

The ‘COPD and Me’ tool is a living document and a number of future developments are being planned, including telehealth and individual smoking cessation inserts. Terry Robinson and her colleagues are confident that 'COPD and The questionnaire, which was administered to a total of 50 Me' will allow respiratory patients with a confirmed diagnosis of COPD, showed professionals in the North evidence of widespread misunderstandings EVIDENTIA •

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13

European Society of Cardiology - by Peter Mas-Mollinedo Reporting from the ESC meeting, Stockholm

Increased risk of MI early in winter sports vacations

A

study carried out by cardiologists from the Medical University of Innsbruck has investigated the risk of myocardial infarction amongst winter sports tourists to the Tyrolean Alps. The research shows that inadequate preparation for the intense physical exertion required, combined with the effects of altitude and low temperature, leads to an increase in heart attack incidents, particularly during the first two days of vacation.

“Every year, millions of tourists visit the Tyrolean Alps to participate in a variety of winter sports, each of which carries a certain risk of accident and injury” explains Doctor Bernhard Metzler, Associate Professor for Cardiology at the university, and senior author of the report.

“Previously it had been shown that sudden cardiac death accounts for a staggering 40% of the total fatalities amongst winter sport tourists in the Austrian Alps and, of these, acute myocardial infarction is the leading cause. We were especially interested in the characteristics of patients admitted to our emergency department with heart attack symptoms so that we could study the trigger mechanisms

and begin to develop preventative strategies.”

The research team reviewed data from over 1,500 patients admitted to the hospital with cardiac conditions between 2006 and 2010.

170 of these - mostly from Germany and the Netherlands - had suffered a heart attack during their winter sports vacation, and this group formed the basis of the detailed study. They were questioned to establish background information about residency, personal details and medical history, as well as the circumstances under which they experienced the initial symptoms. Further investigation then determined whether these symptoms occurred during physical activity.

The results showed an average stay of eight days in the Tyrolean Alps. Interestingly, the majority of acute heart attacks (some 56%) occurred within the first two days of beginning intense physical exercise, yet just 19% had a known cardiac condition. The study also revealed that more than 50% of the patients were physically less active prior to the vacation compared to minimum levels recommended by the European Society of Cardiology. Altitude appears to be a major factor, with heart attacks occurring at a mean of 1,350 metres compared to a mean of residency of just 170 metres.

Finally, some 70% of the study population displayed at least two of the classic risk factors of cardiac artery disease, including smoking, diabetes and hypercholesterolaemia.

The first author of the study, Doctor Gert Klug, also from the Medical University of Innsbruck, offers the following explanation, “The fact that most of the infarcts happened in the very early phase of the vacation hints at a causal relationship between lack of preparation for the intense regime of physical exertion and exposure to high altitudes and low ambient temperatures. From previous studies, it is known that each of these factors might trigger acute myocardial infarction.”

The authors conclude that tourists should adopt a regime of careful preparation with regular physical activity when planning a winter sports vacation. They recommend a gradual increase in physical activity at the vacation resort to lower the risk of heart attack.

Dr. Klug concludes, “An assessment of risk factors and individual patient education might be advisable in patients with multiple risk factors, even if no coronary artery stenosis is known. Prospective data on this topic, however, is still lacking.”

Cardiovascular prevention - is it worth the money?

C

ardiovascular disease (CVD) in all its forms is the biggest cause of death across Europe. Although there is little doubt that better focus on prevention can lessen its impact, we are left with a series of fundamental questions….to what extent can the impact be reduced, and at what cost? And are the health benefits of prevention worth the investment? The EUROASPIRE III health economics study aims to find out.

In Europe, more than four million deaths are directly caused by CVD each year. Not only is it the main cause of death, treatment of CVD also consumes a significant proportion of national

14

health care budgets. Consequently, it imposes a huge burden on both the patients affected and the wider society that foots the bill. Yet through improved control of risk factors, as described in clinical practice guidelines issued by the Joint European Societies, cardiovascular prevention can reduce the impact of CVD. Lowering the risk can be achieved by modifying lifestyle (for instance by undertaking more physical activity or by stopping smoking), as well as through the use of statins, antiplatelet therapies, antithrombotic strategies, ACE inhibitors and β-blockers.

Research lead, Professor Lieven Annemans of Ghent University, recognises the growing conflict between what societies are able to pay

EVIDENTIA • VOLUME 4 • ISSUE 6 • NOVEMBER/DECEMBER 2010

for healthcare and the population’s need for that healthcare. He says, “Societies can no longer afford to pay for major investments in health that deliver only minor benefits. We need to think in terms of health economics, and find the best way to spend the monies available in order to produce as much ‘health’ as possible. Healthcare needs to be seen almost as a productive sector, where the aim is to ensure that people live longer and more healthily.”

In this scenario, priority would be given to those interventions that result in the greatest amount of health for the money that is invested CONTINUED ON PAGE 16 >

Not all ARBs are the same. When you need an ARB, you need to choose one that you and your patients can rely on.

In head-to-head comparison trials, Amias (candesartan) has been proven to reduce blood pressure significantly more than losartan.1-5 What’s more, candesartan is the only ARB proven to reduce both mortality and chronic heart failure hospitalisations in patients with symptomatic C HF (LVEF ≤40%)* irrespective of background therapy, including beta-blockers.6 Give your patients an ARB you can rely on. Give them candesartan.

candesartan cilexetil

For hypertension and heart failure www.heartzone.co.uk *As an add-on to ACE-inhibitors or when ACE-inhibitors are not tolerated.

Prescribing Information – Amias® (candesartan cilexetil) (Refer to Summary of Product Characteristics before prescribing) Amias® (candesartan cilexetil) Abbreviated Prescribing Information Presentation: Tablets containing 2mg, 4mg, 8mg, 16mg or 32mg candesartan cilexetil. Indication: Essential Hypertension in adults; Treatment of adult patients with heart failure and impaired left ventricular systolic function (LVEF ≤ 40%) as add-on therapy to ACE-inhibitors or when ACE-inhibitors are not tolerated.

Dosage: In hypertension: Starting and usual maintenance dose is 8mg od with or without food. Most of the antihypertensive effect is attained within 4 weeks. In some patients, whose blood pressure is not adequately controlled, the dose may be increased to 16mg od and to a maximum of 32mg od. No dose adjustment is necessary in the elderly. A starting dose of 4mg is recommended for patients with renal impairment (including haemodialysis), with mild to moderate hepatic impairment and those at risk of hypotension due to intravascular volume depletion. In heart failure: Usual starting dose is 4mg od with or without food. Up-titration to the target dose of 32mg od or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks. No dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion, renal impairment or mild to moderate hepatic impairment. Amias can be administered with other heart failure treatment including ACEinhibitors, beta-blockers, diuretics and digitalis or a combination of these. The combination of an ACE inhibitor, a potassium sparing diuretic (e.g. spironolactone) and Amias is not recommended and should be considered only after careful evaluation of the potential benefits and risks. Safety and efficacy of Amias not established in children. Contra-indications: Hypersensitivity to any

component of Amias. Second and third trimesters of pregnancy.

Severe hepatic impairment and/or cholestasis. Warnings and Precautions: Monitoring of serum potassium and creatinine levels is recommended during dose titration of Amias in patients with heart failure and regularly in patients taking concomitant ACE-inhibitors and potassium sparing diuretics such as spironolactone. Periodic assessments of renal function is also recommended especially in elderly heart failure patients ≥ 75 years and in heart failure patients with impaired renal function.

Hypotension may occur during treatment with Amias in heart failure patients. Risk of increased blood urea and serum creatinine in patients with renal artery stenosis. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment. Amias should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted.

Possible hypotension during anaesthesia and surgery. Not recommended in patients with primary hyperaldosteronism. As with other vasodilators, use with caution in patients with aortic and/or mitral valve stenosis or obstructive hypertrophic cardiomyopathy. Amias should not be initiated during pregnancy.

When pregnancy is confirmed, treatment with Amias should be stopped immediately, and, if appropriate, alternative therapy commenced. Amias is not recommended during breastfeeding.

Drug Interactions: No clinically significant interactions identified with hydrochlorothiazide, warfarin, digoxin, oral contraceptives, glibenclamide, nifedipine and enalapril. Possible interaction with NSAIDs. Anti-hypertensive effect of Amias may be enhanced by other antihypertensives. Use with lithium is not recommended. If the combination proves necessary, careful

monitoring of serum lithium levels is recommended. Increase in serum potassium may occur with potassium supplements and potassium sparing diuretics. Side-effects: In hypertension clinical trials, adverse events were mild and transient with the overall incidence similar to placebo. Overall incidence showed no association with dose or age. Adverse events commonly seen in clinical trials and postmarketing include: respiratory infection, dizziness/vertigo and headache. Adverse reactions seen very rarely include: Leukopenia, neutropenia, agranulocytosis, hyperkalaemia, hyponatraemia, nausea, increased liver enzymes, abnormal hepatic function or hepatitis, angioedema, rash, urticaria, pruritus, back pain, arthralgia, myalgia, renal impairment/failure, cough, decreased haemoglobin and increased creatinine and urea.

In heart failure clinical trials (e.g. CHARM), the adverse event profile of Amias was consistent with the pharmacology of the drug and health status of the patients. In the CHARM clinical programme, 21% of the Amias group and 16.1% of the placebo group discontinued treatment due to adverse events. Adverse reactions commonly seen in clinical trials and postmarketing were: hyperkalaemia, hypotension and renal impairment/failure. Adverse reactions seen very rarely include leukopenia, neutropenia, agranulocytosis, hyponatraemia, dizziness, headache, nausea, increased liver enzymes, abnormal hepatic function or hepatitis, angioedema, rash, urticaria, pruritis, back pain, arthralgia and myalgia. Legal Category: POM. Packs and Basic NHS Price: Blister packs. Amias 2mg, £3.58 for 7 tablets (PL 16189/0001); Amias 4mg, £3.88 for 7 tablets and £9.78 for 28 tablets (PL 16189/0002); Amias 8mg, £9.89 for 28 tablets (PL 16189/0003); Amias 16mg, £12.72 for 28 tablets (PL 16189/0004); Amias 32mg, £16.13 for 28 tablets (PL 16189/0007). PI Date Code: 10/2010 PI Approval Code: TA1009101 Marketing

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

Please refer to the summary of product characteristics for details on the full side-effect profile and drug interactions of Amias.

Adverse events should be reported.

Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to Takeda UK Ltd. References: 1. Lacourcière Y et al. Am J Hypertens 1999; 12: 1181-1187. 2. Gradman AH et al. Heart Dis 1999; 1(2): 52-7. 3.

Bakris G et al. J Clin Hypertens 2001; 3: 16-21. 4. Vidt DG et al. J Hum Hypertens 2001; 15: 475-480. 5. Andersson OK and Neldam S. J Hum Hypertens 1997; 11(Suppl 2): S63-S64. 6. Young JB et al. Circulation 2004; 110: 2618-2626.

Code: TA101149b Date of preparation: November 2010

European Society of Cardiology - by Peter Mas-Mollinedo Reporting from the ESC meeting, Stockholm

Assessing the risks of bleeding from antithrombotic therapy

A

ntithrombotic therapy using antiplatelet and anticoagulant agents is the cornerstone of treatment for acute and chronic coronary artery disease (CAD), yet it is also associated with an increased risk of bleeding. It is paradoxical that elderly patients, the most likely population to develop CAD, are those that suffer most from bleeding complications. Research has been carried out at OLVG Hospital in the Netherlands into the stratification of risk for all patients requiring this type of therapy.

Professor Freek Verheugt led the research.

“Until relatively recently, aspirin used to be the only effective antiplatelet drug, but now CAD patients can get increased protection from ADP receptor antagonists added to aspirin,” he said.

“Previous studies showed us that, compared to younger patients, the elderly seemed to benefit more from single antiplatelet therapy with aspirin that from dual antiplatelet therapy. This data, however, should be treated with caution since it is derived from post-hoc analysis of randomised control trials.”

The TRITON and PLATO clinical trials demonstrated that newer ADP blockers such as prasugrel and ticagrelor are more effective that clopidogrel. But in both trials, the benefits seemed to reduce in patients over 75 years, although this observation comes from post-hoc analyses of the mega-trials. Other research has also shown that the elderly do not get the full benefit from platelet glycoprotein IIb/IIIa receptors, including abciximab, eptifibatide and tirofiban.

For anticoagulants, there is less data available on the risk of bleeding in relation to age. In elderly patients with fibrinolysis, low molecular weight heparin increases the bleeding risk in the elderly significantly over un-fractionated heparin. So, if chosen as the most effective treatment, low molecular weight heparin should be administered in lower doses for older patients. Bleeding associated with the newer

‘

Until relatively recently,

aspirin used to be the only effective antiplatelet drug, but now CAD patients can

get increased protection from

Cardiovascular prevention is it worth the money? < CONTINUED FROM PAGE 14

– in simple terms, interventions that are the most cost-effective or can prove their value. In Europe, this concept of cost-effectiveness is gaining more and more appeal, and it has an increasing influence upon the pricing and reimbursing of technologies, drugs and interventions.

To evaluate health economics, the net costs of investments are compared with the current alternatives, and the ratio between net costs and net health benefits is then assessed. Many countries have developed guidelines to assist researchers in conducting health economic evaluations, but not all countries handle the assessment of technologies, drugs and interventions in the same way. In some, health economic evaluations are mandatory, while in others, they are merely recommended. And some countries do not regard them as important at all. Healthcare decision makers,

16

however, consider them very useful.

Seven European countries (Belgium, Bulgaria, Finland, France, Italy, Poland and U.K.) are participating in the EUROASPIRE III health economics study. Professor Annemans says, “Through this study, our aim is to assess the cost-effectiveness of prevention in patients with and without established CVD, by following the Joint European Societies’ guidelines. It will tackle both primary and secondary prevention of cardiovascular disease in two separate analyses.

The study will also help to identify the drivers of the relationship between the costs and effects of prevention, and will also model the health and economic outcomes of prevention compared with the current situation.”

Funding: European Society of Cardiology

EVIDENTIA • VOLUME 4 • ISSUE 6 • NOVEMBER/DECEMBER 2010

ADP receptor antagonists

’

added to aspirin.

anticoagulant bivalirudin also increased in the elderly, when compared to younger patients.

The research concludes that the risk of bleeding is increased by antiplatelet and anticoagulant therapy when applied to the treatment of acute and chronic CAD. Professor Verheugt explained the findings, “For aspirin, it was clearly shown that the risk reduction of ischaemic endpoints applies equally to the elderly, but for clopidogrel this benefit is less apparent. Neither was it clearly seen from use of newer ADP receptor blockers such as prasugrel and ticagrelor. Additionally, no clear benefit was observed for elderly patients treated with glycoprotein receptor blockers for acute coronary syndromes.”

Antiplatelet therapies carry an increased risk of bleeding, especially in the elderly. This is probably also true for anticoagulant drugs, but data that specifically covers the elderly is relatively scarce.

Heart Failure Congress report Reporting from the HFC, Berlin

Registry data suggest survival benefit for candesartan

S

ystolic heart failure patients treated with candesartan had better oneyear survival than those taking losartan regardless of dose, comorbidities, or background heart failure treatments, registry data showed.

Survival rate at one year for the 2,639 patients taking candesaratan was 90% compared with 82% for the 2,500 treated with losartan. The difference was significant at P=0.001, said Maria EklindCervenka, MD, of the Karolinska Institute in Stockholm. The one-year survival for the 357 patients taking valsartan (Diovan) was 88%, which was not significantly different from the candesartan survival, Eklind-Cervenka reported at the Heart Failure Congress in Berlin.

‘

In multivariate analysis,

that 150mg is the optimal target dose for losartan, and Eklind-Cervenka said an analysis using the 150mg optimal dose found that losartan was still associated with higher allcause mortality than candesartan (HR 1.4, P=0.002). Acknowledging that it is not possible to make clinical recommendations on the basis of registry data, Eklind-Cervenka said that in her own practice, "I prescribe candesartan, not losartan." But Wayne Levy, MD, of the University of Washington, said that he doubted the study findings. "The mortality difference is about 30%, but in the CHARM trial (candesartan versus placebo) the reduction in mortality was only 12% against placebo."

(The CHARM trial, which was reported at the European Society of Cardiology in 2003 found a 9% relative reduction in mortality compared with placebo, and an absolute difference of 1%.) Levy, who was not involved in the current study, said it was difficult to understand how a

registry trial that compared two active treatments could demonstrate a greater benefit than a placebo-controlled trial. "I am concerned about confounding," he said.

Eklind-Cervenka's results were, he said, "probably due to chance." Asked about this, Eklind-Cervenka agreed that the mortality benefit was much greater than the benefit found in randomised trials, but she speculated that "this perhaps is due to the difference between randomised trial patients and real world patients."

Disclosure: Eklind-Cervenka said she had no potential conflicts of interest. The study was investigator initiated and funded by the Karolinska Institute.

Eklind-Cervenka, M. Choice of angiotensin receptor blocker affects mortality in heart failure - analysis of 5823 patients in the Swedish Heart Failure Registry.

HFC2010; LBT-7.

hazard ratios for mortality compared to candesartan

were 1.7 for losartan (P=0.001) and 0.9 for

’

valsartan (P=0.853).

"In multivariate analysis, hazard ratios for mortality compared to candesartan were 1.7 for losartan (P=0.001) and 0.9 for valsartan (P=0.853)," she said. The average age of patients receiving the angiotensin receptor blockers (ARBs) was 74 and 39% were women. Elkind-Cervenko adjusted hazard ratios for ARB dose, age, gender, aetiology, NYHA class, blood pressure, heart rate, ejection fraction, duration of heart failure, hemoglobin, creatinine, and presence or absence of diabetes, atrial fibrillation, lung disease, hypertension, and treatment with an ACE inhibitor, beta-blocker, or aldosterone antagonist. Recent studies have suggested

Oncology.med 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 ‘Oncology.MED’

EVIDENTIA • VOLUME 4 • ISSUE 6 • NOVEMBER/DECEMBER 2010

17

European Association for the Study of Diabetes - by Dr. Julie Eastgate Reporting from the EASD meeting, Stockholm

Diabetic neuropathy: The winding road from early detection to timely prevention

T

he Camillo Golgi lecture at the 46th annual meeting of the European Association for the Study of Diabetes was presented by Dr Dan Ziegler from Dusseldorf University. Dr Ziegler’s presentation considered ‘Diabetic neuropathy: The winding road from early detection to timely prevention’.

Diabetic neuropathy presents two problems, neuropathic symptoms and associated impairment; neuropathic deficiencies often lead to late diabetes complications such as foot ulcers and amputation; these are associated with increased mortality and morbidity and have considerable cost implications. The DIAD study linked cardiac autonomic neuropathy with a 4-fold increased risk of dangerous

complications and sensory neuropathy with 2-3 fold increased risk. In the ACCORD study neuropathy was a key predictor of excess mortality even during intensive anti-diabetic therapy. The MONICA/KORA study of individuals with prediabetes identified a gradual increase in the incidence of clinically-relevant polyneuropathy with a 13% incidence in individuals with impaired glucose tolerance rising to 28% in those newly diagnosed with diabetes; a 1.2% incidence of painful neuropathy has been estimated in individuals with normal glucose tolerance, that reaches 4.2% in those with impaired fasting glucose, 8.7% in those with impaired glucose tolerance and 13.3% in those with diabetes.

The favoured approach to managing diabetic

neuropathy should be to target both impairment and symptoms early, using diseasemodifying interventions to prevent late complications. This relies on the ability to detect early neuropathic signs. This can be problematical as different nerve fibres operate via different sensory routes and need to be assessed with different tools (sensory/motor nerve conduction velocity, thermal perception, vibration threshold perception). However, all parameters identify neuropathic deterioration in a proportion of individuals with newlydiagnosed diabetes; further on skin biopsy a reduction in the number of intra-epidermal nerve fibres can be demonstrated in patients with early-stage diabetes. Other examples of early neuropathic impairment include:

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Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Takeda UK Ltd.

Please refer to the summary of product characteristics for details on the full side-effect profile of Actos.

Further information is available from Takeda UK Ltd, Takeda House, Mercury Park, Wycombe Lane, Wooburn Green, High Wycombe, Bucks HP10 0HH. Tel: 01628-537900 Legal category: POM Date of preparation: September 2010 Code: AC100862a

18

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actos

®

pioglitazone HCl

Thinking of tomorrow, today

The use of pioglitazone in Type 2 diabetes

A

poster session at the 46th Annual meeting of the European Association for the Study of Diabetes considered research into the findings of two studies on the use of pioglitazone in patients with Type 2 diabetes.

‘

Patients receiving triple combination therapy experienced a lower incidence of oedema and did not see a notable increase in body weight.

’

The PIOcomb study considered the comparative efficacy and safety of three combination therapy regimens, comprising: pioglitazone and insulin, metformin and insulin, and the triple agent regimen of pioglitazone, metformin and insulin. Interim analysis of the double-blind, multi-centre study considered 78 patients with Type 2 diabetes who were previously receiving insulin. Treatment was guided by the goal of achieving a normal fasting glucose level. After 6 months on study treatment haemoglobin A1c (HbA1c) level remained stable for the dual combination

•

Reduced baroreflex sensitivity indicative of autonomic dysfunction.

• Diabetic gastroparesis causing delayed gastric emptying; 22% of patients with Type 2 diabetes and 18% of patients with Type 1 diabetes have evidence of gastric neuropathic impairment despite a lack of symptoms.

• Cognitive dysfunction can be demonstrated in a proportion of patients at the time of diabetes diagnosis. It is thought that reduced cerebral glucose uptake leads to central nervous system dysfunction.

Key to reducing the development of neuropathy is effective long-term glycaemic control, starting early in the disease process; effective glycaemic control has been confirmed as beneficial in those with Type 1 diabetes but

therapy groups but decreased significantly for patients receiving the triple combination (from 7.3% to 6.8%). The daily insulin dose required increased significantly from 37 to 41IU for patients receiving metformin and insulin and decreased significantly for those receiving pioglitazone and insulin (from 37 to 29IU) and triple combination therapy (from 36 to 28IU).

The use of pioglitazone in a combination regimen improved insulin sensitivity and β-cell function. Patients receiving triple combination therapy experienced a lower incidence of oedema and did not see a notable increase in body weight.

A second aspect of PIOcomb was to consider the effect of combination therapy on chronic systemic inflammation, as an indication that the pathophysiological processes associated with the progression of Type 2 diabetes can be modulated by treatment. In particular, reducing chronic systemic inflammation may be able to impact on the development of the macrovascular complications associated with Type 2 diabetes.

Treatment with pioglitazone was associated with a consistent statistically-significant reduction in the levels of C-reactive protein and E-selectin. The levels of other inflammatory markers showed either a significant improvement in just one of the pioglitazone treatment groups or a numerical tendency for improvement that did not reach statistical significance. No tendency for a reduction in inflammatory marker levels was seen

for patients receiving metformin and insulin.

The PIOren study considered the use of pioglitazone as add-on therapy to insulin in patients with Type 2 diabetes who require haemodyalysis. In patients with clinically significant kidney disease insulin pharmacokinetics are altered and vascular insulin resistance is common, which can compromise therapy. Interim analysis of the use of the insulin-sensitiser in this randomised, double-blind, placebo-controlled trial showed that pioglitazone was able to effect a 32% reduction in the dose of insulin required from baseline (p<0.05) and achieve clinically relevant reductions in HbA1c (0.62%, p<0.01), fasting plasma glucose (56mg/dL, p<0.05) and triglyceride levels (111mg/dL, p<0.05) and an increase in adiponectin level (6.9mg/L). No change in ultrafiltrate volume was associated with pioglitazone treatment.

Early results from these studies indicate that aggressive combination therapy regimens that include pioglitazone are effective at improving glycaemic control and reducing insulin requirement; pioglitazone may have the added advantages of improving β-cell function and reducing chronic systemic inflammation. These characteristic indicate the potential for such regimens to modify the course of Type 2 diabetes, reduce the likelihood of patients developing diabetic complications and improve prognosis in those with late stage disease.

not for those with Type 2 diabetes. In those with Type 1 diabetes and poor glycaemic control, loss of conduction in motor nerves is estimated

glycaemic control have neuropathic symptoms within 5 years of diagnosis, but after 15 years a third are affected and after 24 years two-thirds are affected.

Current approaches to the management of diabetic neuropathy comprise symptomatic treatments, such as anti-depressants, anticonvulsants, and opioids. However only 50-60% of individuals are helped by these agents.

Pathogenic approaches to the treatment of diabetic neuropathy have not been developed and agents able to stop progression of the condition have yet to be identified. Given the limited therapeutic options, preventing the development of diabetic neuropathy by optimal glycaemic control represents the best management approach.

‘

Key to reducing the

development of neuropathy is effective long-term

’

glycaemic control.

to occur at a rate of 0.5m/second per year.

Patients with good glycaemic control can keep their level of neuropathy risk at that seen for healthy individuals. Few patients with poor

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19

European Association for the Study of Diabetes - by Dr. Julie Eastgate Reporting from the EASD meeting, Stockholm

Clinical aspects of diabetic foot

A

poster session at the annual meeting of the European Association for the Study of Diabetes considered clinical aspects of diabetic foot.

Three posters considered aspects of detection and prognosis of diabetic foot problems: • Acquati et al. considered the effectiveness of a diabetic foot screening programme implemented in Italy from 2006-2008.

Screening stratified patients with diabetes into 4 risk levels, based on international guidelines. Overall 42% of patients had the lowest level of risk, 22% had a moderately low level of risk, 26% were at moderate risk and 9% were at high risk of diabetic foot complications. Increasing risk was numerically associated with poorer glycaemic control and longer disease duration and as such improved glycaemic control represents a key approach to preventing the development of diabetic foot complications.

• Kono et al. described the findings of ASIPAC FOOT STUDY-2, which considered the characteristics of diabetic patients with Charcot foot in the western Pacific region.

•

Most patients presenting with Charcot foot had prior history of ulcers or amputation and about 50% presented with mid-foot deformity or ulcer on diagnosis. The time from presentation to diagnosis varied between countries (0.5 to 10.9 months) and after the start of treatment the condition often progressed.

Individuals in the western Pacific region who develop Charcot foot receive diagnosis later and have poorer prognosis than those in Western countries, which could be improved by increasing awareness of the potential for individuals with diabetes to develop Charcot foot.

Cho et al. described a study showing that pulse wave velocity at the brachial-ankle, an indicator of peripheral artery disease, is a prognostic indicator of successful foot ulcer healing in patients with Type 2 diabetes.

Ulcers healed in 31 of 86 patients, with a mean healing time of 5.2 weeks. Pulse wave velocity was significantly lower (1553cm/s vs.

1768cm/s, p<0.05) in patients whose ulcers healed. Univariate analysis indicated that brachial-ankle pulse wave velocity correlated with ulcer healing rate (r=0.283, p<0.05).

The findings suggest that systemic arterial stiffness is a predictor of ulcer healing potential in patients with T2D.

When considering treatment outcomes for patients with diabetic foot ulcers: • Soliman et al. considered diabetic foot treatment in patients at different centres in north-west England. They identified a significant degree of variability in healing rate; in one centre more patients experienced full healing of their ulcer within 12 weeks, which appeared to be associated with increased use of a cast despite a higher incidence of neuropathic ulcers. Better treatment outcomes were seen despite comparable rates of infection, osteomyelitis and amputation.

• Fejfarova et al. considered the impact of the type of off-loading in patients with diabetic foot ulcers. The 48 patients included in the study were characterised according to whether off-loading implemented half-shoes, other orthoses or wheelchairs. Patients with an ulcer reported significantly lower physical capacity than the general population, though no difference was reported for the study groups. However, the duration of diabetic foot ulcer was significantly longer in patients using orthoses (33 months) and half-shoes (15 months) versus those in wheelchairs (7 months, p<0.01).

The studies indicated that variable management practices for diabetic foot complications are in place in different countries and different regions within countries, and impact on patient outcome.

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 20

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Gentle yet Strong

A soothing cream with the antimicrobial power to deal with Staph aureus associated with atopic eczema.

Eczmol contains 1% chlorhexidine gluconate which is highly active against Gram positive bacteria, especially Staph aureus, a clinically significant trigger factor in the pathogenesis of atopic eczema. the gentle cream base spreads easily and evenly and is quickly absorbed into the skin.

Eczmol 1% w/w Cream: Abbreviated Prescribing Information Presentation: Please refer to the full Summary of Product Characteristics before prescribing. Indications: Eczmol 1% Cream is an antimicrobial emollient which can also be used as an alternative to soap in the management of dry and pruritic skin conditions including eczema and dermatitis. Dosage: For external use only. For adults, the elderly, infants and children. For application to the skin: Apply Eczmol to the affected areas as often as necessary. For use as a soap substitute: Eczmol may also be used as a cleanser in the bath or shower, or for other toiletry purposes, instead of ordinary soap or shower gel. Contraindications: Preparations containing chlorhexidine are contraindicated for patients who have previously shown a hypersensitivity reaction. However, such reactions are

uncommon. Do not use in cases of known sensitivity to any of the ingredients. Warnings and Precautions: For topical application only. Keep out of the eyes and ears and avoid contact with the brain and meninges. Hypersensitivity to some of the ingredients of Eczmol may be more common in patients with leg ulcer or stasis dermatitis. Eczmol should therefore be used in caution in these patients. Eczmol contains the ingredient cetostearyl alcohol which may cause local skin reactions (e.g. contact dermatitis). Adverse events (see SPC for full list): Irritative skin reactions can occasionally occur. Generalised allergic reactions to chlorhexidine have also been reported but are uncommon. Packaging size and price: 250ml HDPE bottle. ÂŁ3.70. MA Number: Eczmol 1% w/w Cream PL06831/0242. Date of preparation: January 2010. Further

1% chlorhexidine gluconate w/w cream

ANtIMICRoBIAL EMoLLIENt AND SoAP SUBStItUtE information available from the MA holder: Genus Pharmaceuticals Limited, Park View House, 65 London Road, Newbury, Berkshire, RG14 1JN. API.ECZ.V1

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Genus Pharmaceuticals on 01635 568400.

Date of preparation: March 2010 ECZ0110659

GENUS

British Association of Dermatologists - by Samuel Peters Reporting from the BAD annual meeting, Manchester

Acne and increase risk of suicide: isotretinoin may not be to blame

P

atients with acne appeared to have an increasing risk of suicide albeit one that was not statistically significant three years before isotretinoin treatment started, which lasted through six months post-treatment, according to Anders Sundstrom, PhD, of the Karolinska Institute in Stockholm, and colleagues.

They reported online in BMJ that the finding "motivates a close monitoring of patients for suicidal behaviour for up to a year after treatment has ended."

However, they noted that patients with a history of suicide attempts before isotretinoin treatment made new attempts to a lesser extent than did those who started such behaviour in connection with treatment. Thus, they wrote, "patients with severe acne should not automatically have isotretinoin treatment withheld because of a history of attempted suicide." Anecdotal reports have suggested an association between isotretinoin, depression, and suicidal behaviour, the researchers said, but observational studies have not drawn similar conclusions.

So to assess the risk of attempted suicide before, during, and after treatment with isotretinoin for severe acne, the researchers conducted a retrospective cohort study of Swedish databases totaling 5,756 patients ages 15 to 49 who were prescribed isotretinoin.

Patients were observed for 17,197 person-years before treatment, 2,905 person-years during treatment, and 87,120 person-years afterwards. A total of 128 patients were admitted to the hospital for attempted suicide, and a total of 24 committed suicide. The researchers found that between three years and one year before the start of treatment, the risk of suicide attempts gradually rose, although none of the odds ratios were statistically significant, because they straddled the confidence interval. One year before treatment, for instance, patients were at a 57% increased

‘

risk of suicide attempts (95% CI 0.86 to 2.63) and a 36% increased risk of first suicide attempts (95% CI 0.65 to 2.50). The risks became significant during treatment and up to six months afterward (OR 1.78, 95% CI 1.04 to 2.85 for all attempts, and OR 1.93, 95% CI 1.08 to 3.18 for first attempts). After that, risks decreased again, so that three years after treatment was stopped, the observed number of suicides was close to the expected number and remained so during 15 years of follow-up, the researchers said (OR 1.04, 95% CI 0.74 to

natural course of severe acne or to negative effects of the treatment," they wrote. They added that since the rate dropped within two to three years after treatment, successful treatment could have attenuated the suicidal behaviour due to severe acne.

Yet they cautioned that they still "can't exclude the possibility that raised risk of suicide attempts during treatment and six months after treatment is due to the exposure to isotretinoin.

However, a more probable interpretation is that the underlying severe acne may best explain the raised risk."

The study was limited because the researchers had no information on the effects of the treatment and thus could not correlate suicide attempts with treatment effect or lack thereof. The study also only included suicide attempts that resulted in hospital admission. In an accompanying editorial, Parker Magin, MD, of the University of Newcastle in Callaghan, Australia, and John Sullivan, MD, of the University of New South Wales in Sydney, wrote that the study "provides valuable insights into the absolute risk of treatment with isotretinoin," and calls attention to the fact that "acne is not a trivial condition." They added that clinicians can draw "important, practical conclusions" from the study, such as the fact that during and after treatment, "patients should be carefully monitored for depression and suicidal thoughts."

The study was supported by the Swedish Research Council. The researchers reported no conflicts of interest.

The editorialists have in the past three years been members of All About Acne, a group supported by unrestricted educational grants from several drug companies.

Considering the increasing risk of attempted suicide during the years before treatment, we cannot state whether the continued rise during and immediately after treatment was due to the natural course of severe acne or to negative effects of the treatment.

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1.43 for all attempts, and 0.97, 95% CI 0.64 to 1.40 for first attempts). The researchers also observed that patients who made their first suicide attempt before treatment didn't have their suicidal behaviour reinforced during or after treatment and only 38% made new attempts or committed suicide during followup. On the other hand, 71% of those who made a first attempt during treatment or within six months of treatment end made a new attempt or committed suicide during follow-up.

The researchers calculated that the number needed to harm was 2,300 new six-month treatments per year for one additional first suicide and 5,000 per year for one additional repeat attempt. They concluded that the data "support our hypothesis that severe acne, regardless of exposure to isotretinoin, carries an increased risk of attempted suicide."

"Considering the increasing risk of attempted suicide during the years before treatment, we cannot state whether the continued rise during and immediately after treatment was due to the

NOVEMBER/DECEMBER 2010

’

References: Sundstrom A, et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study" BMJ 2010; DOI: 10.1136/bmj.c5812.

Magin P, Sullivan J. Suicide attempts in people taking isotretinoin for acne. BMJ 2010; 341:c5866.

Skiers must always wear sun block Skiers and snowboarders should always wear sunscreen even when the sun is hiding behind the clouds, researchers say.

E

ven though ultraviolet (UV) radiation is generally lower in winter than in summer, it still varies substantially and sun protection behaviours don't always increase proportionally to the weather, Peter Andersen, PhD, of San Diego State University, and colleagues reported in the Archives of Dermatology.

"Adults should be encouraged to wear sunscreen on cloudy days because UV is still high and conditions can change rapidly," Andersen and co-authors wrote.

They said that many people inaccurately associate temperature and cloud cover with UV, which makes skiers and snowboarders vulnerable to sunburn and all of its potential consequences. To measure the prevalence of UV radiation and record sun-protection behaviours, the researchers collected data on 3,937 skiers and snowboarders at 32 highaltitude ski resorts in western North America from 2001 to 2003. They measured direct, reflected, and diffuse UV at 487 points using handheld meters, and interviewed study participants about their sun protection measures as they rode chairlifts to the tops of the mountains. The researchers said that average UV radiation was, as expected, moderate to low during the winter, although there was a large variation. "UV radiation was dangerously high on many late winter and early spring days when UV readings of up to 10 were observed," Andersen and colleagues wrote.

They found that the strongest predictors of UV were temporal proximity to noon, clear skies, and deviation from the winter solstice. UV peaks on the summer solstice and is lowest at the winter solstice, they explained. Ironically, they said, altitude and latitude had more modest associations with UV. Temperature had only a small positive relationship with UV, they added. "It was surprising that UV was less strongly related to latitude and altitude than other variables," Andersen and co-authors wrote while noting that all the resorts in the study were located at latitudes between 34ºN and 50ºN at altitudes ranging from 76.2 to

4,158.4 miles above sea level. They also found that sun-protection behaviours on ski slopes didn't consistently increase when UV levels were elevated. For example, while most adults wore more sunscreen and reapplied it more often on the slopes when UV was higher, such as on sunny days at noon, they didn't often wear hats or protective clothing, or use lip balm on those days, the researchers said. They added that when skiers and snowboarders were more adequately protected like covering more of their bodies and using goggles it likely had more to do with the cold temperatures. "Ironically, these excellent sun safety behaviours are more likely on cloudy days when UV is a bit lower and less likely on sunny days when UV is higher," they wrote. Andersen and colleagues concluded that winter sports practitioners need reminders to rely more on season and time of day when judging UV and the need for sun safety. The study highlights the importance of counseling patients to wear UV protection

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every day all year round especially if they are participating in outdoor activities at higher altitudes, and especially if they are at higher risk for skin cancer.

The study was supported by grants from the National Cancer Institute.

Co-authors reported relationships with Antisense Therapeutics, sanofi-aventis, Bayhill Pharmaceuticals, BioMS, Daiichi-Sankyo, GlaxoSmithKline, Genmab Biopharmaceuticals, Eli Lilly, Medivation, Ono Pharmaceuticals, PTC Therapeutics, Teva, Vivus, Alexion, Accentia, Bayer, Barofold, CibaVision, BiogenIdec, Diagenix, Novartis, UCB Pharmaceuticals, Enzo Pharmaceuticals, Peptimmune, Sandoz, Somnus Pharmaceuticals, and Visioneering Technologies.

Reference: Andersen PA, et al. Environmental cues to UV radiation and personal sun protection in outdoor winter recreation. Arch Dermatol 2010; 146(11): 1241-1247.

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Smoking Cessation report - by Claire Payne

Nicotine dependence and pharmacological interventions: a review

T

here is an undisputed worldwide consensus on the inherent dangers of smoking with tobacco use having gained the dubious mantle of the leading cause of preventable death in the majority of developed countries.

In an exhaustive review of current literature, leading author Dr. Katherine Brennan PhD., Environmental Science and Research Ltd., Poirua, Wellington, New Zealand aimed to examine the role of specific nicotinic receptors in the development of nicotine dependence (ND) allowing an evaluation of the three main pharmacological smoking cessation treatments with action on nicotinic receptors.

There are three stages of ND: 1. The initial experience of acute nicotine 2. The chronic exposure stage 3. The withdrawal phase upon smoking cessation - each characterised by distinct underlying neurological mechanisms.

Following both positive and negative effects of smoking in stage 1, biological dependence is thought to occur during stage 2 where constant exposure to nicotine in the CNS results in the development of neuroadaptations and the process of smoking becomes reinforcing.

Finally, on the withdrawal of nicotine, an individual is likely to experience a ‘negative mood state’ with unpleasant effects such as cravings, irritability and anxiety while the neurological system attempts to rectify the imbalances caused by the withdrawal. The danger of relapse is very high at this point.

Brennan and her team looked at the primary target of nicotine, the acetylcholine nicotinic receptors (nAChRs) located in parts of the brain such as the Ventral Tegmental Area (VTA), the subtypes of which play a role in different stages of the ND cycle. One such subtype, the α4β2 receptor, has emerged as a key player in the reinforcing or ‘rewarding’ effects of nicotine use as it facilitates the transmission of dopamine (DA), long known for its role in the sensation of pleasure. In addition, α4β2 receptors also have a unique

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ability to become upregulated after chronic nicotine exposure resulting in an increased affinity and sensitivity to an agonist such as nicotine. This key role has highlighted α4β2 receptors as a potential therapeutic target for pharmacological smoking cessation therapies.

Nicotine replacement therapy (NRT) is one such therapy. It works by occupying the α4β2 receptors and maintaining them in an upregulated state. Available as a transdermal patch, a nasal spray and chewing gum it has

‘

...on the withdrawal of nicotine, an individual is likely to experience a ‘negative mood state’ with unpleasant effects such as cravings, irritability and anxiety...

’

increased short-term cessation rates by 5070%. It reduces the severity of withdrawal symptoms as well as producing unpleasant effects such as nausea, palpitations and altered respiration when patients smoke concomitantly. Of the three presentations the transdermal patch appears to be the most widely accepted however, relapse rates of up to 95% have been seen despite the initial benefits. The long-term effectiveness of the patch has been described as ‘marginal’, even when the nicotine dose and the treatment period were increased. This may be due to decreased dopaminergic transmission on withdrawal of the patch as the α4β2 receptors in the VTA are suddenly bereft of nicotine and are left without stimulation.

Another smoking cessation treatment bupropion, an antidepressant drug with ‘atypical’ properties, has shown superior efficacy relative to NRT. It exerts an antagonistic effect on nAChRs resulting in a decrease in the

NOVEMBER/DECEMBER 2010

reinforcing effects of nicotine and has the additional benefit of alleviating depression, an unpleasant symptom of nicotine withdrawal and one which reliably predicts relapse.

Bupropion is more complex in its action than NRT as it affects both dopaminergic and noradrenergic pathways. This action results in a reduction of VTA DA cell firing and inhibition of the stimulatory effects of nicotine on the brain-reward pathways. Interestingly, the addition of NRT to bupropion treatment has shown significant clinical efficacy over either treatment alone.

The most recently approved agent, varenicline, is an analogue of the plant-derived (Cystisis labarnum or ‘false tobacco’) nicotinic agonist cysticine. As a partial α4β2 receptor agonist, it is thought that varenicline has a direct modulatory effect on the mesolimbic DA system. This system is highly implicated in the development of ND. It has also shown an antagonistic effect which, together with its agonist properties, creates a ‘ceiling effect’ on DA release stabilising the mesolimbic dopaminergic system and thereby reducing DA-induced craving or withdrawal symptoms.

Varenicline has shown superior efficacy to both bupropion and NRT and in a recent metaanalysis involving nearly 5,000 participants the odds of long-term abstinence rates were increased threefold.

In the future, successful pharmacological treatments may have to take into account the individual variations in response to treatments.

So far, there is evidence to suggest that there are differences in nAChR sensitivity to nicotine but how much this contributes to the varied responses seen to smoking cessation treatments is unknown.

Reference: 1. Brennan KA, Lea RA, Fitzmaurice PS, Truman P. Review: Nicotinic receptors and stages of nicotine dependence. J Psychoparmacol 2010; 24:793 originally published online Feb 27, 2009 (found at http://sagepub.com/cgi/content/abstract/24/6/793) DOI: 10.1177/026988100256

NEW DATA 91% of middle-aged smokers exhibit one or more symptoms of COPD2 Smoking cessation is the single most effective intervention to reduce risk of COPD development and progression3 50

Continuous abstinence rate weeks 9-12 (%)

CHAMPIX can help your mild to moderate COPD patients stop smoking1

42.3%

40

CHAMPIX vs. placebo OR = 8.4 (95% CI: 4.99-14.14), p<0.0001

30 20

8.8%

10 0

CHAMPIX 1 mg bd (n=248)

placebo (n=251)

In a 27 centre, double-blind, multinational study investigating patients with mild-moderate COPD who smoked an average of 24 cigarettes/day over the past month for an average of 41 years:1* CHAMPIX provided ~8x greater odds of stopping smoking after 12 weeks of treatment vs. placebo (OR = 8.40; 95% CI: 4.99-14.14, p<0.0001)1 After one year, 18.6% of patients treated with CHAMPIX remained smoke-free, vs. 5.6% treated with placebo (OR = 4.04; 95% CI: 2.13-7.67, p<0.0001)1 *Adapted from Tashkin D et al. Presented at CHEST, 2009. A 27 centre, double-blind, multinational study investigated CHAMPIX vs. placebo for smoking cessation in mild to moderate COPD patients (postbronchodilator FEV1/FEV <70% and FEV1% predicted normal value ≥50%). Subjects received either CHAMPIX 1 mg bd or placebo for 12 weeks, with a 40-week non-treatment follow-up. Primary endpoint was CO-confirmed continuous abstinence rate for weeks 9–12. Mean patient baseline characteristics (±SD): number cigs/day over past month 24 (±11); smoking duration 41 (±9) years.

CHAMPIX® Film-Coated Tablets (varenicline tartrate) ABBREVIATED PRESCRIBING INFORMATION – UK. (See Champix Summary of Product characteristics for full Prescribing Information). Please refer to the SmPC before prescribing Champix 0.5 mg and 1 mg. Presentation: White, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 0.5” on the other side and light blue, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 1.0” on the other side. Indications: Champix is indicated for smoking cessation in adults. Dosage: The recommended dose is 1 mg varenicline twice daily following a 1-week titration as follows: Days 1-3: 0.5 mg once daily, Days 4-7: 0.5 mg twice daily and Day 8-End of treatment: 1 mg twice daily. The patient should set a date to stop smoking. Dosing should start 1-2 weeks before this date. Patients who cannot tolerate adverse effects may have the dose lowered temporarily or permanently to 0.5 mg twice daily. Patients should be treated with Champix for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment at 1 mg twice daily may be considered. Following the end of treatment, dose tapering may be considered in patients with a high risk of relapse. Patients with renal insufficiency: Mild to moderate renal impairment: No dosage adjustment is necessary. Patients with moderate renal impairment who experience intolerable adverse events: Dosing may be reduced to 1 mg once daily. Severe renal impairment: 1 mg once daily is recommended. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 1 mg once daily. Patients with end stage renal disease: Treatment is not recommended. Patients with hepatic impairment and elderly patients: No dosage adjustment is necessary. Paediatric patients: Not recommended in patients below the age of 18 years. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions: Effect of smoking cessation: Stopping smoking may alter the pharmacokinetics or pharmacodynamics of some medicinal products, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). Changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, depression, suicidal ideation and behaviour and

Date of preparation: January 2010 CHA851b ©Pfizer 2009

suicide attempts have been reported in patients attempting to quit smoking with Champix in the post-marketing experience. Not all patients had stopped smoking at the time of onset of symptoms and not all patients had known pre-existing psychiatric illness. Champix should be discontinued immediately if agitation, depressed mood or changes in behaviour or thinking that are of concern for the doctor, the patient, family or caregivers are observed, or if the patient develops suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after discontinuation of varenicline was reported, although in some cases the symptoms persisted; therefore, ongoing follow up should be provided until symptoms resolve. Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine withdrawal. In addition, smoking cessation, with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness (e.g. depression). The safety and efficacy of Champix in patients with serious psychiatric illness has not been established. There is no clinical experience with Champix in patients with epilepsy. At the end of treatment, discontinuation of Champix was associated with an increase in irritability, urge to smoke, depression, and/or insomnia in up to 3% of patients, therefore dose tapering may be considered. There have been post-marketing reports of hypersensitivity reactions including angioedema and reports of rare but severe cutaneous reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients using varenicline. Patients experiencing these symptoms should discontinue treatment with varenicline and contact a healthcare provider immediately. Pregnancy and lactation: Champix should not be used during pregnancy. It is unknown whether varenicline is excreted in human breast milk. Champix should only be prescribed to breast-feeding mothers when the benefit outweighs the risk. Driving and operating machinery: Champix may have minor or moderate influence on the ability to drive and use machines. Champix may cause dizziness and somnolence and therefore may influence the ability to drive and use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their

ability to perform these activities. Side-Effects: Adverse reactions during clinical trials were usually mild to moderate. Most commonly reported side-effects were abnormal dreams, insomnia, headache and nausea. Commonly reported side-effects were increased appetite, somnolence, dizziness, dysgeusia, vomiting, constipation, diarrhoea, abdominal distension, stomach discomfort, dyspepsia, flatulence, dry mouth and fatigue. See SmPC for other less commonly reported side effects. Overdose: Standard supportive measures to be adopted as required.

Varenicline has been shown to be dialyzed in patients with end stage renal disease, however, there is no experience in dialysis following overdose. Legal category: POM Basic NHS cost: Pack of 25 11 x 0.5 mg and 14 x 1 mg tablets Card (EU/1/06/360/003) £27.30. Pack of 28 1 mg tablets Card (EU/1/06/360/004) £27.30. Pack of 56 0.5 mg tablets HDPE Bottle (EU/1/06/360/001) £54.60. Pack of 56 1 mg tablets HDPE Bottle (EU/1/06/360/002) £54.60. Pack of 56 1 mg tablets Card (EU/1/06/360/005) £54.60. Not all pack sizes may be marketed / marketed at launch. Marketing Authorisation Holder: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom. Further information on request: Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS. Last revised: 11/2009. Ref: CI7_0.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Pfizer Medical Information on 01304 616161.

For further information, please contact Pfizer Medical Information on 01304 616161 or email medinfo.uk@pfizer.com References: 1. Tashkin D et al. Efficacy and safety of varenicline for smoking cessation in patients with mild to moderate Chronic Obstructive Pulmonary Disease (COPD). Poster Abstract Presented at CHEST, Oct 31st - Nov 5th, 2009, San Diego, California: Abstract 1054. 2. Calverley PMA. COPD: Early Detection and Intervention. Chest 2000; 117:365S-371S. 3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Pocket guide to COPD diagnosis, management and prevention. A guide for healthcare professionals. Updated 2008.

Cardiology report - by Peter Mas-Mollinedo

Nurses reduce risk of recurrent complications: results from the RESPONSE trial

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six-month outpatient prevention programme conducted by nurses has resulted in significant and sustained improvements in the control of cardiovascular risk factors, including high cholesterol or high blood pressure, in patients hospitalised for a heart attack or impending heart attack.

The programme, applied in addition to standard medical care, led to the improved adherence to current guidelines on prevention, including lifestyle and compliance with drug treatment. The nurses were able to increase the proportion of patients with good control of risk factors by 40% (defined as at least seven out of nine risk factors on target) and to reduce the calculated risk of dying in the next 10 years by about 17%.

RESPONSE (Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists) was an 11-centre randomised study designed to quantify the impact of a nurse-coordinated outpatient risk management programme on the risk of future clinical events in patients with symptomatic coronary artery disease. The primary endpoint was patient evaluation according to the SCORE risk score at 12 months, with secondary endpoints assessed according to the Framingham risk score and individual risk factors at 12 months follow-up (including lipid profile, glucose, blood pressure,

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weight, waist circumference, physical activity, healthy diet, alcohol consumption).

In explaining the background to the trial, principal investigator Professor Ron Peters from the Academic Medical Centre, Amsterdam, said: "Patients with coronary artery disease are at high risk of recurrent complications and death. Preventive care can effectively reduce this risk, and guidelines have been issued by the American Heart Association/American College of Cardiology and the European Society of Cardiology which target common risk factors for heart disease such as high blood pressure, smoking, and high cholesterol.

"Together, these risk factors are associated with the development of coronary artery disease, which remains the world's leading cause of death. At present, a considerable gap exists between these guidelines and their application in clinical practice. It is widely believed, both by patients and doctors, that the preventive aspect of treatment is given insufficient priority and that new approaches are needed to realise the full benefits of prevention.

A short coaching programme by a nurse, on top of usual care, is such a new approach already found promising in primary care."

The RESPONSE trial, which evaluated an outpatient nursing programme in 11 hospital centres in the Netherlands, included 754 patients hospitalised for an acute coronary complication (MI or impending MI). They were randomised to either usual care alone or usual care plus a sixmonth nursing intervention that included four extra visits to the outpatient clinic.

Nurses gave advice on healthy lifestyle (food choices, physical exercise, non-smoking, weight control), and monitored major risk factors, such as blood pressure, cholesterol

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and sugar levels, and use of preventive medication. The nurses pursued specific targets as defined by the guidelines, and if necessary drug treatment was adjusted in collaboration with treating physicians.

The primary measurement of the study was performed at 12 months, which was six months after the last visit to the nurse. Results showed a significant improvement in risk factor prevalence at the end of the programme, with no loss of effect at 12 months.

Overall, at 12 months after the start of the programme, 35% of patients in the nursing group and 25% of patients in the control group were classified as having good control of risk factors (defined as at least seven out of nine factors on target). This reflects an increase of 40%. Of the risk factors targeted by the intervention, body weight was the least successful. There was no change in weight or waist circumference between baseline and 12 months, with no difference between the two study groups. "This may indicate that weight loss is not a realistic target in the first year after a coronary event," said Professor Peters, "when priority needs to be given to several other risk factors. It remains to be seen if later attempts might be more successful."

When the risk of death over the next ten years was calculated according to the SCORE risk function, the nurses were able to reduce this risk by 17%.

Professor Peters noted that these results were achieved against a background of medical care that was better than expected, with risk factor levels in the study population more favourable than those reported in the literature - and with excellent adherence to medication in both groups. This high level of care in the control group, he added, may have been influenced by participation in the trial.

"The nurse programme was practical and well attended by the patients," he said. "More than 93% of patients attended all visits to the nurse. These findings are very encouraging and support the initiation of prevention programmes by nurses to help patients reduce their risk of future complications."

EMA Highlights - by Gary Finnegan

Emerging Uses of EMA-Approved Drugs REGULATOR FACES LEADERSHIP VACUUM

with day-to-day running of the agency and will not affect the medicines approval process.

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NEW MEDICINES APPROVED

he European Medicines Agency (EMA) is headed for uncertain times after a row over the pay grade of its executive director has left it without a leader for the first half of next year.

The outgoing chief, Thomas Lonngren, will stand down on December 31 having served two five-year terms. The move was well flagged but the EMA and European Commission have spent months wrangling over the salary for Lonngren’s replacement, leading to the withdrawal of earlier advertisements for the post.

“There will be a gap,” said Lonngren.

“Now I have only got a few months left and a procedure like this takes quite a long time, so we cannot expect a replacement until June or July next year.”

The recruitment process has been marred by a series of missteps. The European Commission first advertised the position in January but had to cancel that posting due to incorrect translation.

The post was then advertised again but this too was pulled after the EMA objected to the Commission’s decision to downgrade the job to a lower pay grade. Brussels wanted to class the job as AD14 instead of AD15 – the top grade for European civil servants.

After weeks of internal debate, it has been agreed that Lonngren’s successor will be paid at AD15 level, meaning they can expect to earn up to €199,000.

After coming under fire for the delay, the EMA released a statement acknowledging that Lonngren would not be replaced for several months but said its head of administration, Andreas Pott, would act as executive director until the recruitment process is completed.

The power vacuum comes at a time when the Agency is in the midst of reforms designed to make it more transparent and better connected to regulators outside Europe.

Europe’s London-based medicines watchdog employs around 500 staff but while the absence of a permanent director could stall key strategic decisions, it is less likely to interfere

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he EMA’s Committee for Medical Products for Human Use (CHMP) has given its backing to a new influenza vaccine for children.

Fluenz, a live attenuated nasal vaccine from MedImmune LLC, is intended for the prophylaxis of influenza in children from 24 months to less than 18 years of age.

The CHMP also approved an extension of therapeutic indications for a number of products: - Lucentis (ranibizumab), from Novartis Europharm Ltd, to include the treatment of visual impairment due to diabetic macular oedema; - Sprycel (dasatinib), an orphan medicine from Bristol-Myers Squibb Pharma EEIG, to include the treatment of adult patients with newly diagnosed Philadelphia chromosomepositive chronic myelogenous leukaemia in the chronic phase; - Sutent (sunitinib), from Pfizer Ltd, to include the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults.

CHMP BACKS HARMONISED PRESCRIBING INFORMATION

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he Agency’s human medicines committee has recommended the harmonisation of the prescribing information for three drugs. The reviews were initiated because of differences in the summaries of product characteristics, labelling and package leaflets in countries where the products are marketed.

The affective medicines are: - Fortum (ceftazidime), from GSK and associated companies. The medicine is an antibiotic authorised for treatment of EVIDENTIA •

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infections such as hospital acquired pneumonia, complicated skin and soft tissue infections, bone and joint infections, chronic otitis media, complicated intra-abdominal infections, meningitis and complicated urinary tract infections, and bacteraemia that is associated with these infections.

- Tazocin (piperacillin/tazobactam), from Pfizer and associated companies. The medicine is an antibiotic authorised for treatment of infections such as severe pneumonia, complicated urinary tract infections, complicated intra-abdominal infections, complicated skin and soft tissue infections and bacteraemia that is associated with these infections.

- Vascace Plus and associated names (cilazapril/hydochlorothiazide), from Roche and associated companies. The medicine is authorised for treatment of hypertension in patients whose blood pressure is not adequately controlled with cilazapril alone.

EMA U-TURN ON FABRAZYME ADVICE The CHMP has reviewed its previous advice on the use of Fabrazyme (agalsidase beta) during an ongoing supply shortage. Fabrazyme is used to treat the rare, inherited enzymedeficiency disorder, Fabry disease.

Temporary treatment recommendations to manage patients relying on this medicine have been in place since the start of the supply shortage and have been regularly updated.

However, the Committee has decided to reverse its recommendation that doctors administer a lower dose of the drug due to the shortage.

The decision was triggered by an increase in reported adverse events in patients treated with the lower dose of Fabrazyme.

“The CHMP is now recommending that physicians switch back to prescribing the full dose of Fabrazyme according to the authorised product information, depending on the availability of enzyme replacement therapy and the severity of the disease,” the EMA said in a statement.

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www.nejm.org

INVESTIGATIVE DRUG INDUCES REGRESSION OF METASTATIC MELANOMA WITH MUTATED BRAF GENE

A Reporting from some of the latest articles in

Journal Reviews by Bruce Sylvester

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Phase 1 clinical trial of PLX4032, an experimental targeted drug to treat metastatic melanoma tumours with a specific genetic signature, showed a clinical effect in over 80% of patients. The findings appeared recently in the New England Journal of Medicine.

PLX4032 is an inhibitor of a protein called BRAF, which is overactive in more than half of all melanomas.

"Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients," said Keith Flaherty, MD, director of Developmental Therapeutics at the Massachusetts General Hospital (MGH) Cancer Center, lead author of the study. "Until now, available therapies were few and unreliable, so these findings can really change the outlook for patients whose tumours are fueled by this mutation."

Surgery usually successfully treats earlystage melanoma, but once the skin tumour has spread to other sites in the body, the prognosis is been poor. FDA-approved drugs – interleukin-2 and dacarbazine – produce a response in only 10 to 20% of patients. The current prognosis for survival in metastatic melanoma is 9 months or less.

The role in melanoma of the BRAF mutation – which keeps the protein constantly activated and driving cell growth – was discovered in 2002. When one potential drug targeting BRAF was ineffective, investigators began studying PLX4032, an agent developed by Plexxikon and licensed to Roche Pharmaceuticals. Initial trial results were disappointing, but a new formulation that increased the bioavailability of PLX4032 led the new results reported in the NEJM. The initial stage of the Phase 1 study was designed to establish the effective dose.

Investigators enrolled 55 cancer patients, most with metastatic melanoma, who received escalating doses of PLX4032 until unacceptable side effects occurred. BRAF mutations were present in the melanomas of 16 subjects, and 11 achieved tumour shrinkage; in one instance, the tumours disappeared. Three participants with BRAF-mutated thyroid cancers also had their tumours shrink or stabilise in response to PLX4032 treatment.

In the second stage of the Phase 1 study,

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investigators enrolled 32 patients with BRAFmutated melanoma. They received the PLX4032 dosage established in the first phase, 960mg twice a day.

In 26 of those participants, tumours shrank more than 30%, meeting the criteria for clinical response, and completely disappeared in two subjects.

Since another two participants had some reduction in the size of their tumours, the investigators projected that PLX4032 would shrink tumours in approximately 90% of patients with BRAF-mutated melanomas.

"One of the things that make these results truly remarkable is that this drug works so reliably," he explains. "And patients who have been experiencing symptoms like pain and fatigue begin to feel better within a week of starting treatment, giving them a much better quality of life.

Resistance to PLX4032 developed in the tumours of many subjects, leading to resumed tumour growth. Currently tumour suppression has been maintained from about three months to longer than two years, with an average progression-free survival of eight months. More studies will explore how resistance occurs and potential strategies to get around it.

BMJ

British Medical Journal www.bmj.org

BLOOD TEST PREDICTS PROSTATE CANCER DEATH RISK UP TO 25 YEARS IN ADVANCE

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blood test at the age of 60 can predict a man’s risk of dying from prostate cancer within during the next 25 years, according to researchers at Memorial Sloan-Kettering Cancer Centre, in New York, and Lund University, in Sweden.

The findings were published recently online in the British Medical Journal.

The investigators analysed blood samples from 1,167 men born in 1921; the samples were collected between 1981 and 1982 as part of the Malmö Preventive Project in Sweden.

All subjects were followed until they had reached age 85 or had died. After studying various biomarkers, the researchers found that the PSA level was a highly accurate predictor of long-term risk. PSA testing has been recommended for the early detection of prostate cancer for many years. This finding suggests that a baseline PSA could determine who should and should not continue to be screened for prostate cancer.

"We were hoping to find a novel marker," said lead researchers Andrew Vickers, PhD and Hans Lilja, MD PhD. "What we found instead was a new way of using an old test."

From all subjects, 126 men were diagnosed with prostate cancer, and of those, 90% of deaths occurred in men in the top 25% of PSA levels at age 60. The researchers concluded that men with a PSA level above 2ng/ml at age 60 should be considered at increased risk of aggressive prostate cancer and should continue to be screened regularly.

The investigators reported that subjects with a PSA level below 1ng/ml had a 0.2% chance of death from prostate cancer. They concluded that men with PSA levels in this range (about half of all men) should be deemed at low risk of prostate cancer death and might not need to be screened in the future. The study also showed that some men found to be at low risk developed prostate cancer, but it was not likely to cause symptoms or shorten their life by the age of 85.

"This is a key finding," said Dr. Vickers. "We know that screening detects many prostate cancers that are not harmful, leading to anxiety and unnecessary treatment. It is our ability to determine the risk of the really aggressive cancers that makes this approach of such great potential value."

www.thelancet.com

ENDARTERECTOMY AND STENTING ARE SAFE FOR YOUNGER PATIENTS

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meta-analysis of existing research suggests that, while stenting for carotid stenosis should be avoided in patients aged 70 years or older, it could be as safe as endarterectomy in younger patients.

The findings appeared online recently in The Lancet. Professor Martin M Brown, National Hospital for Neurology and Neurosurgery and the Institute of Neurology, University College London, UK, undertook the meta-analysis with colleagues involved in major carotid stenting trials.

Despite results from earlier, individual studies, Brown and colleagues believed these previous studies were not of sufficient size to establish relative safety of stenting versus endarterectomy in specific patient subgroups.

The researchers evaluated data from all 3,433 patients with symptomatic carotid stenosis from three trials, the EVA-3S , SPACE, and ICSS studies. The primary outcome event was any stroke or death.

In the first 120 days after randomisation, any

stroke or death was 53% more likely to occur in the stenting group than in the carotid endarterectomy group (153 [8·9%] of 1725 allocated stenting; 99 [5·8%] of 1708 allocated endarterectomy).

Of all subgroup variables evaluated by the reserachers, only age significantly modified the treatment effect. They found that in patients younger than 70 years, the estimated 120-day risk of stroke or death was similar in both groups (50 [5·8%] of 869 patients allocated stenting; 48 [5·7%] of 843 allocated endarterectomy). However, in patients 70 years or older, the estimated risk with carotid stenting was twice that with carotid endarterectomy (103 [12·0%] of 856 vs 51 [5·9%] of 865.

Risk estimates of stroke or death within 30 days of treatment among patients younger than 70 years were similar for both groups (5·1% after stenting vs 4·5% after endarterectomy); in patients 70 years or older, the estimates were 10·5% after stenting vs 4.4% after endarterectomy.

The authors concluded: “The harm of stenting strongly depended on age; whereas estimated risks of stroke or death in patients younger than 70 years were similar in the two treatment groups, we noted that the risk of stenting doubled among patients 70 years or older compared with the younger age group.

By contrast, the risk of stroke or death associated with endarterectomy was similar in old and young patients…in conclusion, there is strong evidence that, in the short term, the harm of stenting compared with endarterectomy decreases with younger age.”

Journal of the American Medical Association www.jama.ama-assn.org

LIFESTYLE WEIGHT LOSS STRATEGIES ARE EFFECTIVE FOR OVERWEIGHT ADULTS

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ifestyle interventions, including physical activity and structured weight loss programmes can result in significant weight loss for overweight, obese and severely obese adults, researchers report. The findings appeared recently in JAMA, the Journal of the American Medical Association.

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programmes or evidence-based treatment guidelines, particularly for severe obesity.

In an intensive lifestyle intervention study of diet and physical activity, Bret H. Goodpaster, Ph.D., from the University of Pittsburgh School of Medicine and colleagues, randomised 130 severely obese adult individuals without diabetes to two groups in order to evaluate weight loss during one year. They randomised one group of subjects to diet and physical activity for the entire 12 months; the other group had the same dietary intervention, but physical activity was delayed for six months. The study was conducted from February 2007 with follow-up through April 2010.

"To facilitate dietary compliance and improve weight loss, liquid and pre-packaged meal replacements were provided at no cost for all but one meal per day during months one through three and for only one meal replacement per day during months four through six of the intervention," the authors reported.

Physical activity included brisk walking up to 60 minutes, five days a week. Subjects were given a pedometer and encouraged to walk at least 10,000 steps a day. The researchers also provided small financial incentives for adherence to the exercise intervention. The participants received group, individual and telephone contacts during the lifestyle intervention.

"Of 130 participants randomised, 101 (78 %) completed the 12-month follow-up assessments," the authors state. The group that started with the diet and physical activity lost more weight in the first six months than the delayed-activity group (about 24 pounds as compared to 18 pounds). However, the authors report that weight loss at 12 months was about the same in the two groups (almost 27 pounds versus about 22 pounds). "Waist circumference, visceral abdominal fat, hepatic (liver) fat content, blood pressure and insulin resistance were all reduced in both groups," according to the authors.

"In conclusion, intensive lifestyle interventions using a behaviour-based approach can result in clinically significant and meaningful weight loss and improvements in cardiometabolic risk factors in severely obese persons. It is also clear that physical activity should be incorporated early in any dietary restriction approach to induce weight loss and to reduce hepatic steatosis [fatty liver] and abdominal fat. Our data make a strong case that serious consideration should be given by healthcare systems to incorporating more intensive lifestyle interventions similar to those used in our study. Additional studies are clearly needed to determine long-term efficacy and cost-effectiveness of such approaches."

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Medical news from around the world - by Gary Finnegan

World Health Matters

EUROPEAN UNION NEW GENE VARIANT LOWERS BLOOD PRESSURE A pan-European study has discovered a gene variant which lowers blood pressure, paving the way for new medicines and preventative strategies for hypertension.

People who have the newly-identified gene were found to have 15% fewer strokes, myocardial infarctions and coronary deaths.

The finding is the result of one of the largest ever genetic studies in this field and involved researchers from eight countries.

A total of 40,000 people participated in the research which was led by the University of Glasgow and Istituto Auxologico Italiano of Milan.

The gene variation is found in a gene regulating the production by the kidney of uromodulin, a protein excreted in urine. The variant is found in the UMOD gene in chromosome 16 and protects against hypertension due to its regulation of uromodulin. Individuals carrying the gene variant had less uromodulin in their urine.

The functional role of uromodulin, although

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being one of the major proteins in urines, was until now largely unknown. The study reveals that uromodulin is likely to participate in blood pressure disregulation and to facilitate onset of cardiovascular disease probably by stimulating sodium reabsorption in the kidney and thus increasing sodium in the body.

More than 500,000 variants were analyzed throughout the spectrum of the human genome as part of the project.

While previous genome-wide association studies on high blood pressure had investigated groups of individuals with a wide spectrum of blood pressures, the researchers investigated individuals with extremes of blood pressure, comparing individuals with very high or with fully normal blood pressures. On the whole, genetic data were analysed in 39,706 individuals of European origin– 21,466 with hypertension and 18,240 with normal blood pressure.

The results of the study were published in the Public Library of Science Genetics open-source journal. It is just one part of The Ingenious Hypercare Project, an EU-funded network of excellence integrating 31 research teams from Europe, China and Russia, working on genetics, functional genomics and molecular

‘

The gene variation is found in a gene regulating the production by the kidney of uromodulin, a protein excreted in urine.

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mechanisms of hypertension and hypertensionrelated cardiac and vascular damage.

Genetic variations identified so far by scientists only explain 1-2% of the difference in blood pressure in the population, suggesting the presence of many more variations yet to be discovered.

Reference: PLoS Genet 6(10): e1001177. doi:10.1371/ journal.pgen.1001177

NOVEMBER/DECEMBER 2010

RUSSIA FRACTURES INCREASING DEATH AND DISABILITY RATES A study by the International Osteoporosis Foundation (IOF) has revealed the grim state of post-fracture care in the Russian Federation and predicts a huge increase in osteoporotic fractures to ageing populations.

The preliminary findings of a report published by the IOF looks at figures from Eastern Europe and Central Asia and shows poor diet and health services mean the burden of bone disease continues to grow.

However, the authors note that the lack of fracture registries and diagnostic equipment makes the full extent of the problem difficult to assess.

Population projections for most countries in the region predict that by 2050 there will be a decrease of the total population, but a significant increase (up to 56%) in the percentage of people aged 50 and over. As a result, in the Russian Federation alone the number of people with osteoporosis is expected to increase by a third by 2050.

Despite the major public health burden of osteoporosis-related fractures, the disease suffers from severe under recognition in the region mainly due to the lack of solid epidemiological and economic data which would help convince health authorities of the urgency of osteoporosis prevention.

There are no formal hip or fragility fracture registries in most countries within the region and data on vertebral fractures, the most common osteoporotic fracture, are completely lacking, according to IOF President John Kanis.

“It is clear from the key findings that governments need to support wide scale epidemiological studies to collect data on the incidence of osteoporotic fractures,” he said.

DXA technology, diagnostic equipment which provides the most accurate method of diagnosis, is usually only accessible in main cities. Yet in about one-third of the countries, more than 40% of the population lives in a rural area. In most countries, drug treatment for those at high risk of fracture is not fully reimbursed, effectively making treatment unaffordable for the majority of citizens.

Low levels of calcium and vitamin D intake

impact negatively on bone health. The average daily calcium intake in nearly all countries outlined in the report falls far below the WHO recommendations. In addition the majority of populations in the region suffer from severe vitamin D insufficiency. This not only affects fracture rates, but also causes rickets. In recent years the incidence of rickets (paediatric vitamin D deficiency) among Russian infants has ranged from 54% to 66% in some regions.

Although older people who sustain a hip fracture are at increased risk of death and suffer long-term disability throughout the world, the research indicates that this problem is far more severe in the Russian Federation and in many other countries of the region, said Professor Olga Lesnyak, Vice-President of the Russian Association on Osteoporosis and author of the report.

“There is an urgent need for healthcare providers to improve post hip fracture surgical care,” she added.

Reference: Eastern European & Central Asian Regional Audit, November 2010, International Osteoporosis Federation

CHINA PATIENTS WHO SKIP FLU JAB FAVOUR ALTERNATIVE MEDICINES A new nine-country study has shown a link between older patients who choose not to have the flu vaccine and a preference for traditional health practices.

Patients over 65 who opted out of seasonal flu immunisation programmes were more likely to embrace a range of alternative treatments which they believe will protect them from infection, according to a study by a Hong Kongbased group.

Eating steamed pears, having a soothing massage or bathing in a herbal mixture are just some of indigenous health practices used by older people to ward off or treat influenza, according to research published in the Journal of Advanced Nursing.

Other traditional measures discovered by nurse researchers at the Hong Kong Polytechnic University included being rubbed with a coin, eating cheese, yoghurt and honey and having warm drinks made with ginger or lemon.

The team surveyed nine countries to find out why so many of them were failing to meet the

75% annual influenza vaccination rate recommended by the WHO. “Annual flu epidemics severely affect three to five million people worldwide every year and cause up to half a million deaths, with most deaths in industrialised countries occurring in people over 65,” says co-author Professor Samantha Mei-che Pang from the University's School of Nursing. “That is why it is so important to find out why some older people have the annual flu vaccine, while others decide not to.”

In an effort to control for variations in cultures, healthcare financing systems and flu vaccine uptakes, the study was conducted in China, Indonesia, Greece, Turkey, South Korea, the UK, Canada, Brazil and Nigeria.

A series of focus groups were held with vaccinated and unvaccinated older people aged 65 and older, and seven countries submitted completed questionnaires providing demographic data on 172 participants. This showed that two-thirds of the people who took part had been vaccinated, with vaccination rates highest in Canada (93%) and lowest in Nigeria (31%). Other countries ranged from 44% to 82%.

Those who chose not to be vaccinated said they did not see themselves as vulnerable, were not convinced that the vaccines were safe and effective, believed a healthy lifestyle – including good diet and hygiene practices – would protect them, and were more likely to trust indigenous health practices such as special drinks or foods.

“Our findings support the growing evidence that older people are much more likely to be vaccinated against flu if they feel vulnerable, see flu as a threat and believe that the vaccine will be effective with little, or no, side effects,” says Professor Pang.

“It also revealed a finding that we do not believe has been observed in previous studies: that those who distrust the vaccine's effectiveness are more likely to rely on healthy lifestyles, good hand hygiene and indigenous health practices to protect them from flu,” she said.

Cost was also a factor in countries where free healthcare is not available, Professor Pang added, calling on authorities to step up their efforts to remind older people of the importance of flu vaccination.

NORWAY SEROTONIN DEFICIENCIES LINKED TO ADHD Attention-deficit hyperactivity disorder (ADHD) is more common in children whose mothers are genetically predisposed to have impaired production of serotonin, according to a new Norwegian study.

The University of Bergen studied 459 adult outpatients with ADHD, 97 of their family members and 187 control individuals recruited from across Norway. Participants provided blood samples for gene sequencing along with information about psychiatric diagnoses and symptoms.

By sequencing 646 individuals, the researchers identified nine different mutations, of which eight were significantly associated

‘

The clinical outcome

probably depends on a sum of many different genetic or

’

environmental factors...

Reference:

with impaired function of the enzymes. Family analysis of 38 individuals who carried these mutations and 41 of their offspring revealed that children of mothers who had one of the mutations - and, therefore, had impaired serotonin production - had a 1.5- to 2.5-times higher risk of ADHD than control individuals or offspring of fathers with the mutations.

There was a large variance in the number and severity of symptoms reported by these individuals, suggesting that for offspring of mothers with these mutations, “the clinical outcome probably depends on a sum of many different genetic or environmental factors in addition to variations in maternal serotonin levels.”

The results may have public health implications, the authors note. “Whether it is caused by genetic vulnerability, chronic inflammation, malnutrition or other processes, maternal serotonin deficiency during pregnancy might predispose to neuropsychiatric disorders and cardiovascular illnesses,” they conclude.

Journal of Advanced Nursing. 6610, pp2297-2308.

Reference:

(October 2010)

Arch Gen Psychiatry. 2010; 67[10]: 1033-1043 EVIDENTIA •

VOLUME 4 •

ISSUE 6 •

NOVEMBER/DECEMBER 2010

31

FDA Highlights - by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs STATINS CUT RISK OF HEART DISEASE IN CRPELEVATED PATIENTS

R

esearchers report that persons with a 10-year cardiovascular disease (CVD) risk of 5% or more and normal cholesterol levels but high levels of high sensitivity C-reactive protein (hsCRP) can reduce their CVD risk with statin therapy.

The finding appeared recently in an issue of the journal Circulation: Cardiovascular Quality and Outcomes.

The results come from a sub-analysis of data from the randomised, placebo-controlled, double blind Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER). The trial included men aged 50 years or older and women aged 60 years or older.

The investigators reported that cholesterollowering statin drugs reduced the relative risk of cardiovascular disease (CVD) by 45% for people estimated to have a 10-year CVD risk of 5% to 10%, and reduced the relative risk by 49% among those with an estimated 11% to 20% ten-year risk.

Subjects with a 10-year risk of <5% did not have a statistically significant reduction in events with statins.

"These data demonstrate that women and men with elevated hsCRP who are otherwise at 5% to 20% ten-year risk had substantive risk reductions with statin therapy even though they are currently outside US treatment guidelines," said lead author Paul Ridker, MD, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, Massachusetts.

Dr. Ridker said recent changes in Canadian CVD prevention guidelines led the investigators to seek to better define CVD risk. The Canadian recommendations call for statin therapy for patients who have "intermediate risk," 10% to 19% ten-year risk, and elevated hsCRP, even if their cholesterol levels are in the normal range.

"The new Canadian guidelines are a major step forward for prevention and incorporate

32

EVIDENTIA •

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hsCRP in a thoughtful manner," said Dr. Ridker. "However, intermediate risk was defined in the Canadian guidelines as 10% to 20% ten-year risk, yet we observed major benefits of statin therapy for those with risks of 5% to 10% as well."

He added that many physicians incorrectly consider a 5% to 10% risk score to be "lowrisk," especially in woman who tend to develop CVD at least a decade later than men, even though heart and blood vessel disease remains the number one killer of women and men.

‘

The new Canadian

guidelines are a major step forward for

prevention and incorporate hsCRP in

’

a thoughtful manner.

Investigators in this JUPITER sub-analysis found that although men and women in the 5% to 10% Framingham 10-year risk group got equal benefit from statin therapy, more women tended to be in the 5% to 10% risk group while men tended to be in the 11% to 20% group.

"The current US recommendations label individuals with a >20% ten-year Framingham risk as high risk and advise statin therapy for them," said Dr. Ridker. "Statin treatment for individuals with Framingham risk <20% has until now been less clear-cut."

The new findings support the position of the American Heart Association and the US Centers for Disease Control that hsCRP testing is optimal for people with intermediate risk, in order to enable doctors in treatment decisions.

NOVEMBER/DECEMBER 2010

MEMANTINE HELPFUL TO PATIENTS WITH MILD TO MODERATE LEWY BODY DEMENTIA

M

emantine lessens deterioration and improves behavioural symptoms in patients with dementia with Lewy bodies (DLB), researchers reported in a study published early online and appearing in the recent edition of The Lancet Neurology.

Already used to treat symptoms of Alzheimer’s disease, the research suggests that memantine could become a treatment for symptoms of other brain disorders that involve an excess of glutamate stimulation, such as Lewy-body-related dementias.

Murat Emre, MD, Istanbul University, Istanbul, Turkey, investigated the safety and efficacy of memantine for the treatment of mild to moderate Parkinson's disease dementia (PDD) and DLB. The study lasted 6 months.

The investigators randomised 199 patients (121 PDD and 78 DLB) from 30 centres in Europe to receive memantine 20mg or placebo once a day. They recorded functional, behavioural, cognitive, and global outcome measures at baseline and at the end of weeks four, 12, 16, and 24. Caregivers were also interviewed to assess their strain during the study.

After 24 weeks, more patients treated with memantine achieved improvement in clinical status, compared with the placebo group.

More patients with DLB using memantine had a favourable response; this group showed a significantly greater improvement in global clinical status and behavioural symptoms than those taking placebo.

No significant differences were found between the two treatments in patients with PDD. Also, the investigators reported no significant differences in treatment outcomes associated with activities of daily living, motor symptoms or caregiver burden.

Memantine was generally well tolerated and side-effects were mild and similar in both

groups. Common serious adverse events were stroke (three in the memantine group), falls (two in the memantine group; one in the placebo group), and worsening of dementia (two in the memantine group).

Patients with DLB benefited more from memantine than those with PDD, and the authors suggest that this might be because DLB has more pathological similarities to Alzheimer's disease than does PDD. "On the basis of the results of this study, memantine might be a treatment option in patients with mild to moderate DLB," the authors concluded.

In an accompany comment, Laura Marsh, MD, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas, highlighted the complexity of the clinical management of patients with Lewy-body-related dementias, and that memantine is a symptomatic treatment not a cure. She noted the ongoing need for pharmacological treatments that address cognitive impairment in Parkinson's disease and related disorders, in order to impede development of frank dementia.

ANTIVIRAL THERAPY TREATMENT IN CHRONIC EYE PROBLEMS DUE TO HERPES SIMPLEX VIRUS

T

reatment with oral antiviral medication following infection with the herpes simplex virus (HSV) appears to be related with a reduced risk of recurring eye-related manifestations of the disease, according to research published in the recent issue of Archives of Ophthalmology.

‘

We found a more dramatic protective effect of oral antiviral prophylaxis on recurrences of ocular HSV than had been described previously.

’

After the initial exposure, HSV establishes a latent infection in sensory nerve structures.

Reactivation of this infection can cause initial and recurrent disease in one or both eyes,

including inflammation or infection of the cornea, eyelid, membrane inside the eye or middle layer of the eye.

Ryan C. Young, Mayo Clinic, Rochester, Minnesota, and colleagues estimated the incidence of HSV eye disease in a communitybased cohort, in Olmstead County, Minnesota, from 1976 through 2007. During this time period, they identified 394 patients with ocular HSV, for an annual incidence of 11.8 per 100,000 individuals.

Oral antiviral therapy was prescribed for 175 (44%) of these patients, who underwent therapy for an average of 2.8 years (36% of the average 7.7 years of follow-up).

Patients not receiving prophylactic therapy were 9.4 times more likely to have a recurrence of epithelial keratitis, 8.4 times more likely to have a recurrence of stromal keratitis, and 34.5 times more likely to have a recurrence of blepharitis or conjunctivitis than those taking antiviral medications.

Twenty patients had adverse outcomes, including visual loss and perforation of the cornea. Of these, 17 (85%) were not taking oral antiviral prophylaxis.

"Overall, this community-based retrospective study demonstrated a stable incidence of HSV eye disease during a recent 32-year period," the authors said. "We found a more dramatic protective effect of oral antiviral prophylaxis on recurrences of ocular HSV than had been described previously."

"The results of this study suggest that oral antiviral prophylaxis should be considered for patients with frequent recurrences of corneal disease," they concluded. "Additionally, we recommend an evaluation of the possible barriers preventing compliance with antiviral prophylaxis and a reassessment of the costeffectiveness of long-term oral antiviral therapy."

ADDITION OF ALBUTEROL TO GLATIRAMER ACETATE SHOWS BENEFIT IN PATIENTS WITH MS

A

dding albuterol to standardthereapy glatiramer appears to improve clinical outcomes in patients with multiple sclerosis (MS), researchers reported in the recent issue of Archives of Neurology.

Samia J. Khoury, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, EVIDENTIA •

VOLUME 4 •

Massachusetts, and colleagues assessed the effects of albuterol treatment as an add-on therapy for patients starting treatment with glatiramer acetate. As background, the authors noted that patients with MS have elevated levels of interleukin-12 and that albuterol sulfate may decrease interleukin-12 levels.

They randomised 44 patients to receive daily subcutaneous 20mg/daily injections of glatiramer acetate plus either an oral dose of albuterol 4mg/daily or placebo for two years.

A neurologist evaluated each subject at baseline and at months six, 12, 18, and 24.

Blood samples were taken at baseline and at months three, six, and 12 months. Magnetic

‘ ’ Thirty-nine subjects were evaluable

for this analysis.

resonance imaging (MRI) of the brain was performed at baseline and at 12 months, and 24 months.

Thirty-nine subjects were evaluable for this analysis.

For measures of functional status, there was improvement in the glatiramer acetate plus albuterol group compared with the placebo group at six months and at 12 months, but not at 24 months. Compared with patients taking placebo, those taking albuterol also had a delay in time to first relapse.

Production of two inflammatory markers interleukin-13 and interferon-gamma - decreased in both treatment groups, with a treatment effect on interleukin-13 appearing at 12-months.

Adverse events were generally mild. There were three moderate or severe events related to the treatment, including reaction at the glatiramer acetate injection site, leg weakness, and chest tightness.

"We conclude that treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis," the authors wrote. "The combined regimen seems to enhance clinical response during the first year of therapy."

Sources: American Heart Association, The Lancet Neurology, Archives of Ophthalmology, Archives of Neurology.

ISSUE 6 •

NOVEMBER/DECEMBER 2010

33

by Steve Devrell

No country for old men

J

View from The Waiting Room

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ust over a year ago, I retired from teaching. I was 58 years and 93 days old; at least that’s what my pension print out had calculated. It was the end of 36 ½ years or 7,200 days in the classroom.

When I started teaching, Gary Glitter was a respectable pop star, Sir Alf Ramsey was still manager of England and Maggie Thatcher had yet to plagiarise St. Francis by offering us hope from despair and light from darkness! As I sat on the stage, listening to people making exaggerated claims to my ability and importance, I was just happy to know that I had reached the finishing line with my dignity and integrity still pretty well intact.

I slipped into retirement very easily. I took up new challenges, adopted new projects all without the pressure of time. It was, and still is an idyllic existence. But I had hardly unpacked my garden furniture when the parliamentary rumblings began. The government told me that I should feel bored, depressed, unfulfilled and desperate to get back to work. I’m sorry Mr. Cameron, I do not. There is no way I want to put on a green polo shirt and pat my backside for Asda.

If I am not prepared to be coaxed back into work, then why not play the ‘we can’t afford your healthcare’ card. Some very graphic headlines have appeared lately in the national press. One particular newspaper claimed that ‘of all the threats to human society, including war, disease and natural disaster, one outranks them all and that is the ageing of the human population. No invading army, volcanic eruption or yet undreamt of plague can rival ageing in the breadth or depth of its impact on society. Over the next half century, the proportion of people aged 60 plus around the world is expected to more than double.’

Terms like the demographic agequake are used to graphically describe the situation. But the truth behind the dramatic headlines is sometimes hidden. It is not clear then that the growing ranks of the elderly will necessarily increase costs in all spheres. The Wanless Report on the financing of the NHS, commissioned by the Government and

NOVEMBER/DECEMBER 2010

published in November 2001 pointed out that although healthcare costs rise with age, the ageing population has less of an impact on health spending than most people think.

The reason for this is that on average, about a quarter of all healthcare someone consumes in a lifetime is spent in the last year of their life (whenever that might be) and the cost of this last year tends to fall with increasing age. A recent study in Scotland found that a person who died at 50 had an average £7,000 of health care in his or her final year compared with £3,000 in the last year of a person dying at 90. If this pattern is adopted throughout the country then it would be fair to say that the impact of an ageing population will be to postpone rather than increase health service costs.

Figures show that the number of people reaching the magic 100 years has hardly changed in the past century, but the proportion of people approaching that age has sharply increased. One of the great unanswered questions is whether increasing life expectancy will mean longer, healthy life expectancy or more years spent in declining health and increasing disability. Research in America and Britain suggests the number of old people with severe disability is declining, but other evidence suggests those with minor problems may increase. These minor problems may have been endured in generations gone by, whereas in this more affluent world with greater medical advances, people want to be treated for these minor problems rather than suffer in silence.

A report by the BBC entitled ‘The cost of ageing needs re-calculating,’ published in September 2010, bears out this research. Rising life expectancies and improved health means the population is ageing more slowly and the burden may not be as dramatic as feared.

A joint US and Austrian study concluded that there was need for a new way of measuring ageing which is not reliant on fixed chronological ages. Traditionally, the old-age dependency ratio, OADR (the number of people aged over 65 to people of working age), was used to assess the burden to society of supporting elderly people. The increase of that ratio was considered to reflect the growing

PRESCRIBING INFORMATION – UK AND ROI REBIF® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF® 8.8 MICROGRAMS/0.1ML AND REBIF® 22 MICROGRAMS/0.25ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF® 22 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF® 44 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE Interferon beta-1a

Larger numbers of people still steadily working out in my gym who are well into their seventies. They appear to be no more a drain on health resources than people half their age burden of the ageing population in the pensions system.

The US Austrian study developed a new dependency measure called audit disability dependency ratio (ADDR). It is based on disabilities that reflect the relationship between those who need care and those who are capable of giving it. The study shows that when ageing is measured based on this ratio, the speed of ageing is reduced by four-fifths compared with the conventional OADR. These methods of measurement have policy implications because slow and predictable changes in pension age justified by an increased number of years of healthy life at older ages may be more politically acceptable than large abrupt changes justified on a pure budgetary basis.

At present in the UK the difference between the average age of retirement (63.2 –figures OECD) and life expectancy (79.0 – figures WHO) is just 15.8 years.

Compare these figures with other prominent European countries like France 22.3 years, Italy 19.4 years, Spain 18.7 years and Germany 17.2 years and we clearly have some catching up to do. Yet the government seems determined to reduce the gap further by a fairly steep rise in the pensionable age and a much reduced deal for those on contributory pensions. Perhaps it is the government’s rather unsubtle way of reducing health expenditure in the elderly by re-introducing the ‘pit pony mentality’ whereby people are expected to work until they drop.

In my view, the present retirement age is old enough for anyone. I would like my children to enjoy a longer and even more affluent retirement than myself. This is called progress. The present retirement age is an excellent benchmark for the social

progress that has been made and should not be used as a moveable feast.

From my observations, I am often amazed by the numbers of comparatively young people who are already struggling with health issues. Many of these issues appear to be self-inflicted. Obesity is perhaps the most visual example of self abuse, with the dangers from smoking and excessive alcohol consumption also high on the causes of this premature decline into ill health. I am reluctant to say so, but many of these problems appear to be related to issues of social class, where indulgences give comfort. Perhaps money should be spent on a more aggressive approach to health education so that good habits are learnt early and maintained through life as a matter of course.

Conversely, I have noticed larger numbers of people still steadily working out in my gym who are well into their seventies. They appear to be no more a drain on health resources than people half their age. Their decline is likely to be later and more rapid, which in stark terms is more cost effective to the health industry. I admit these are tendencies rather than rules, but they are important factors in considering the overall cost of health treatment.

On a more controversial note, perhaps it is time that older people should be allowed to choose their own destiny. Why should they be allowed to suffer in order to reach the conclusion we are all destined for. It would certainly be my request to be surrounded by family and loved ones and gently leave this world without having to suffer the pain and indignity of a slow, painful and costly death. But, we may still be a generation or two away from the acceptable ethics of this option.

Presentation Rebif 8.8μg and 22μg: Pre-filled glass syringe containing 8.8μg or 22μg of Interferon beta-1a in respectively 0.2 or 0.5ml. Rebif 22μg or 44μg: Pre-filled glass syringe containing 22μg or 44μg Interferon beta-1a in 0.5ml. Rebif 8.8μg and 22μg: Disposable pre-filled pen injector (RebiDose) containing 8.8μg or 22μg of Interferon beta-1a in respectively 0.2 or 0.5ml. Rebif 22μg or 44μg: Disposable pre-filled pen injector (RebiDose) containing 22μg or 44μg Interferon beta-1a in 0.5ml. Rebif 8.8μg/0.1ml and Rebif 22μg/0.25ml: Pre-filled glass cartridge containing 132μg of Interferon beta1a in 1.5ml. Rebif 22μg/0.5ml or Rebif 44μg/0.5ml: Pre-filled glass cartridge containing 66μg or 132μg of Interferon beta-1a in 1.5ml. Indication Treatment of relapsing multiple sclerosis. Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity. Dosage and administration Initiate under supervision of a physician experienced in the treatment of multiple sclerosis.

Administer by subcutaneous injection. Recommended dose: Weeks 1 and 2: 8.8μg three times per week (TIW); weeks 3 and 4: 22μg TIW; week 5 onwards: 44μg TIW (22μg TIW if patients cannot tolerate higher dose). RebiDose pre-filled pen is for single use and should only be used following adequate training of the patient and/or carer. Follow the instructions provided in the package leaflet. Rebif solution for injection in cartridge is for multidose use and should only be used with the RebiSmart autoinjector device following adequate training of the patient and/or carer. Follow the instructions provided with the RebiSmart device. Limited published data suggest that the safety profile in adolescents aged 12–16 years receiving Rebif 22μg TIW is similar to that in adults. Do not use in patients under 12 years of age. Prior to injection and for 24h afterwards, an antipyretic analgesic is advised to decrease flu-like symptoms. Evaluate patients at least every second year of the treatment period. Contraindications History of hypersensitivity to natural or recombinant interferon beta, or to any of the excipients; treatment initiation in pregnancy; current severe depression and/or suicidal ideation. Precautions Inform patients of most common adverse reactions. Use with caution in patients with previous or current depressive disorders and those with antecedents of suicidal ideation. Advise patients to report immediately any symptoms of depression and/or suicidal ideation.

Closely monitor patients exhibiting depression and treat appropriately. Consider cessation of therapy. Administer with caution in patients with a history of seizures and those receiving anti-epileptics, particularly if epilepsy is not adequately controlled. Closely monitor patients with cardiac disease for worsening of their condition during initiation of therapy. Patients should use an aseptic injection technique and rotate injection sites to minimise risk of injection site necrosis. If breaks in skin occur, patients should consult their doctor before continuing injections. If multiple lesions occur, discontinue Rebif until healed. Use with caution in patients with history of significant liver disease, active liver disease, alcohol abuse or increased serum ALT. Monitor serum ALT prior to the start of therapy, at months 1, 3 and 6 and periodically thereafter. Stop treatment if icterus or symptoms of liver dysfunction appear. Treatment has potential to cause severe liver injury including acute hepatic failure.

Full haematological monitoring is recommended at months 1, 3 and 6 and periodically thereafter. All monitoring should be more frequent when initiating Rebif 44μg. New or worsening thyroid abnormalities may occur. Thyroid function testing is recommended at baseline and if abnormal every 6–12 months. Use with caution in, and closely monitor patients with, severe renal and hepatic failure or severe myelosuppression. Serum neutralising antibodies may develop and are associated with reduced efficacy. If a patient responds poorly and has neutralising antibodies, reassess treatment. Use with caution in patients receiving medicines with a narrow therapeutic index cleared by cytochrome P450.

Women of childbearing potential should use effective contraception. Limited data suggest a possible increased risk of spontaneous abortion. During lactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and give supportive treatment. Side effects In the case of severe or persistent undesirable effects, consider temporarily lowering or interrupting dose. Very common: flu-like symptoms, injection site inflammation/reaction, headache, asymptomatic transaminase increase, neutropenia, lymphopenia, leucopenia, thrombocytopenia, anaemia. Common: injection site pain, myalgia, arthralgia, fatigue, rigors, fever, pruritus, rash, erythematous/maculo-papular rash, diarrhoea, vomiting, nausea, depression, insomnia, severe elevations of transaminase. Serious side effects include: injection site necrosis, hepatic failure, hepatitis with or without icterus, severe liver injury, anaphylactic reactions, angioedema, erythema multiforme, erythema multiformelike skin reactions, seizures, thromboembolic events, thrombotic thrombocytopenic purpura/haemolytic uremic syndrome, suicide attempt, Stevens–Johnson syndrome, dyspnoea, retinal vascular disorders. Consult the Summary of Product Characteristics for more information relating to side effects. Legal category POM. Price Rebif 8.8μg and 22μg: 6 (0.2ml) + 6 (0.5ml) syringes – £552.19. Rebif 22μg: 12 syringes (0.5ml) – £624.77. Rebif 44μg: 12 syringes (0.5ml) – £813.21. Rebif 8.8μg and 22μg: 6 (0.2ml) + 6 (0.5ml) pens – £552.19. Rebif 22μg: 12 pens (0.5ml) – £624.77. Rebif 44μg: 12 pens (0.5ml) – £813.21. Rebif 8.8μg/0.1ml and 22μg/0.25ml: 2 cartridges – £406.61. Rebif 22μg/0.5ml: 4 cartridges – £624.77. Rebif 44μg/0.5ml: 4 cartridges – £813.21. For prices in Ireland, consult distributors Allphar Services Ltd. Marketing Authorisation Holder and Numbers Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/98/063/007; 003; 006; 017; 013; 016; 010; 008; 009. For further information contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: 020 8818 7373. Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: 01 4687590.

Date of Preparation July 2010.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. In the Republic of Ireland information can be found at www.imb.ie.

Adverse events should also be reported to Merck Serono Limited Tel: +44(0)20 8818 7373 or email: medinfo.uk@merckserono.net.

References: 1. PRISMS Study Group. Lancet 1998;352:1498–1504.

2. Kappos L et al. Neurology 2006;67:944–953.

3. Steinberg SC et al. Clin Drug Investig 2010;30(2):89–100.

Date of Preparation: August 2010

REB10–0231

Rebif®: established, effective treatment for people with RRMS1,2 Delivered through innovation to help address adherence Rebif® is available in multidose cartridges for use with the RebiSmart™ electronic autoinjector device Up to 70% of RRMS patients treated with DMDs are non-adherent with therapy*3 RebiSmart™ is the only device in MS which allows adherence to be reviewed

*Retrospective analysis of 1606 RRMS patients treated with interferon-ß-1a (44µg sc tiw or 30µg im qw) or interferon-ß-1b; adherence was defined as a medication possession ratio of ≥85% over a period of 360 days.

RRMS: relapsing–remitting multiple sclerosis. DMD: disease-modifying drug. sc: subcutaneous. tiw: three times weekly. im: intramuscular. qw: once weekly.

Prescribing information can be found overleaf.

Merck Serono is a division of Merck