Evidentia by Peter Mas-Mollinedo

Volume 4 Issue 2 March/April 2010 ISSN 1753-464X

Conference reports from: Liverpool, London, New Orleans and Orlando

First choice for second line

In depression

Cipralex follows first-line treatment. See what follows Cipralex Budget pressures make a generic SSRI a logical first choice in depression. But for some patients, first line doesn’t always work. Fortunately, there’s now a cost-effective second-line choice that is supported by a growing body of independent evidence. Cipralex: One of the most cost-effective SSRIs according to new NICE Guidance1 “...performs* better than citalopram...”, concluded a recent independent review of the evidence for Cipralex by the Cochrane Collaboration 2 One of two antidepressants offering “…the best possible balance between efficacy and acceptability” in patients with moderate to severe depression, stated the largest ever independent multiple-treatments meta-analysis of antidepressants 3 Want to know more? Go on-line at www.challengingdepression.co.uk/ad

Cipralex® Tablets and Oral Drops Prescribing information: Please refer to the full Summary of Product Characteristics before prescribing, particularly in relation to side effects, precautions and contra-indications. Presentation: Tablets containing 5, 10 or 20 mg of escitalopram (as the oxalate). Drops containing 10 mg/ml or 20 mg/ml escitalopram (as the oxalate). Cipralex drops 10 mg/ml, each drop contains 0.5 mg escitalopram. Cipralex drops 20 mg/ml, each drop contains 1 mg escitalopram. Indications: Treatment of major depressive episodes, panic disorder with or without agoraphobia, social anxiety disorder (social phobia), generalised anxiety disorder and obsessivecompulsive disorder. Dosage: Depression: 10 mg once daily. Dose may be increased to a maximum of 20 mg daily. Treatment for at least 6 months is required. Panic disorder: 5 mg for the first week increasing to 10 mg daily and, if needed, 20 mg daily. Maximum effectiveness is reached after about 3 months. Social anxiety disorder: Usual dose 10 mg once daily until symptom relief obtained (usually 2–4 weeks). Dose may be decreased to 5 mg or increased to a maximum of 20 mg daily. Treatment for 12 weeks is recommended. Treatment should be re-evaluated regularly. Generalised anxiety disorder: Usual dose 10 mg once daily. May be increased to a maximum of 20 mg daily. Obsessivecompulsive disorder: Initial dose 10 mg daily, increased to a maximum of 20 mg if required. Elderly (>65 years): Consider using half the recommended dose and a lower maximum dose. Children and adolescents (<18 years): Not recommended. Reduced

hepatic function: 5 mg daily for the first 2 weeks in mild-moderate impairment, increasing to 10 mg if required. Use with caution and careful dose titration in severely impaired hepatic function. Reduced renal function: Use with caution in severely reduced renal function (CLCR <30 ml/min). Contra-indications: Hypersensitivity to escitalopram or excipients. Use in combination with nonselective, irreversible monoamine oxidase inhibitors (MAOIs). Use in combination with reversible MAO-As (moclobemide) or linezolid. Pregnancy and lactation: Do not use in pregnancy unless clearly necessary. Breastfeeding is not recommended. Precautions: Possible risk in ability to drive a car or operate machinery. Alcoholic drinks not advised. Co-administration with serotonergic compounds not recommended. Insulin and/or oral hypoglycaemic dosage may require adjustment. Use with caution in patients: at risk of hyponatraemia; with a history of mania/hypomania; undergoing ECT; with epilepsy; with bleeding disorders or taking medicines that will affect clotting of blood or platelet function; with coronary heart disease. Do not stop treatment abruptly. Closely supervise patients, especially those at high risk, for suicide-related behaviours during first few weeks of treatment, until improvement occurs. Drug interactions: MAOIs, MAO-A and MAO-B inhibitors. Potential interaction with serotonergic medicines (e.g. triptans), lithium, tryptophan, St John’s Wort, omeprazole, esomeprazole, lansoprazole, fluvoxamine, ticlodipine and cimetidine. Caution in poor metabolisers of CYP2C19. Use caution with drugs metabolised by the enzymes CYP2D6 or CYP2C19. Adverse events: Generally

*At weeks 6–12, Cipralex was signiﬁcantly more effective than citalopram in achieving acute response (p=0.006) and remission (p=0.02)2

mild and transient and include nausea, decreased or increased appetite, anxiety, restlessness, abnormal dreams, decreased libido, anorgasmia, insomnia, somnolence, dizziness, paraesthesia, tremor, sinusitis, yawning, diarrhoea, constipation, vomiting, dry mouth, increased sweating, arthralgia, myalgia, ejaculation disorder, impotence, fatigue, pyrexia, increased weight. Anaphylactic reaction, serotonin syndrome, convulsions, suicidal ideation, suicidal behaviour, hepatitis and angioedemas have also been reported. Abrupt cessation may produce discontinuation symptoms. Prescribers should consult the full Summary of Product Characteristics in relation to other side effects. Legal category: POM. Cipralex Tablets 5 mg (PL13761/0008) 28 tablets £8.97; 10 mg (PL13761/0009) 28 tablets £14.91; 20 mg (PL13761/0011) 28 tablets £25.20. Cipralex 10 mg/ml oral drops (PL13761/0019) 1 bottle x 28 ml £18.82; 20 mg/ml oral drops (PL13761/0028) 1 bottle x 15 ml £20.16. Further information available from: Lundbeck Limited, Lundbeck House, Caldecotte Lake Business Park, Caldecotte, Milton Keynes, MK7 8LG. ® Cipralex is a Registered Trade Mark. © 2009 Lundbeck Limited. Date of last revision of PI: May 2009.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Lundbeck Limited, Medical Information, on: 01908 638972.

References 1. NICE. Clinical Guideline 90. Depression in adults (update). October 2009. Available at: http://guidance. nice.org.uk/CG90/Guidance/pdf/English (accessed December 2009). 2. Cipriani A, Santilli C, Furukawa TA et al. Escitalopram versus other antidepressive agents for depression (Review). Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No: CD006532. DOI: 10.1002/ 14651858. 3. Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments metaanalysis. Lancet 2009; 373: 746−758.

Date of preparation of piece: February 2010. 0110/ESC/501/193l

24183 CPX Evidentia 297x210 D aw1.indd 1

1/3/10 10:41:39 Evidentia

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February

Depression Ad

Cipralex

297x210mm (A4)

Bringing clinical evidence to practice in primary and secondary care

CONTENTS 4

COVER STORY

Guest Editorial - COPD exacerbations: What do we really know? By Dr. Richard Russell

Volume 4 Issue 2 March/April 2010 ISSN 1753-464X

Options for therapy after metformin Reporting from the Diabetes UK APC, Liverpool

More evidence of marijuana-psychosis link Psychiatry Report

15 Stepping up therapy improves asthma in children Reporting from the American Academy of Allergy, Asthma and Immunology, New Orleans

18 Allergic rhinitis and quality of life Respiratory Study

Conference reports from: Liverpool, London, New Orleans and Orlando

19 Disease-specific self-management programme trial for

5 Incidence trends in

patients with COPD

childhood diabetes: Reporting from Diabetes UK APC, Liverpool

Reporting from the British Thoracic Society meeting, London

20 Blood pressure that is too low may be harmful Reports from the American College of Cardiology, ASM Orlando

27 EMEA Highlights - Emerging uses of EMEA approved drugs 28 World Health Matters - Medical news from around the world

30 The BIG FOUR - Reporting from some of the latest journal articles 32 FDA Highlights - Emerging Uses of FDA-Approved Drugs 34 View from The Waiting Room - Only the weak survive 15 6

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Guest Editorial Dr. Richard Russell, Consultant Respiratory Physician, King Edward VII Hospital, Windsor and Lecturer, Imperial College, London.

COPD exacerbations: What do we really know?

he COPD exacerbation is a sentinel event. The national COPD audits of 2004 and 20081 we have are accurate, prospective data on outcomes for patients with COPD admitted to hospital. We know that admissions with exacerbations cause significant morbidity and mortality. They consume enormous quantities of resource and lead to disease progression. Exacerbation frequency is a prognostic factor in COPD. However, what do we really know about exacerbations of COPD? Key questions remain to be answered. What causes exacerbations? Can they be prevented? Can they even be predicted? How should they best be managed both from a medical treatment point of view and also from a provision of care perspective? For the past 10 years high quality prospective data has been kept by several academic respiratory departments on COPD exacerbations and now this work is bearing fruit. We are beginning to get some answers and some of this valuable data was presented at the winter scientific meeting of the British Thoracic Society. The causes of exacerbations are not clearly understood. The consensus, supported by experimental and observational models, is that upper respiratory tract viral infection reduces host defence against bacterial growth leading to an increase in bacterial count and an increase in airway inflammation. This is manifest as an increase in mucus production, a change in the nature of the mucus and also an increase in breathlessness. The mainstays of treatments are to increase bronchodilatation, provide antibiotics and corticosteroids. If severe then an attendance at hospital may occur with all its attendant risks and benefits. Can exacerbations be prevented or if detected and treated early, aborted early in their evolution? One novel approach is to use the weather.

Contributors: Maria Dalby, Steve Devrell, Gary Finnegan, Peter Mas-Mollinedo, Bruce Sylvester, Samuel Peters, Dr. Sunil Upadhyay

The meteorological office working in collaboration with respiratory physicians have been interested in patterns of exacerbation, weather and air temperature. A model has been developed whereby patients can be forewarned of a period of increased risk due to cold temperatures.2 This warning was linked to an intervention package giving practical advice on looking out for signs of an exacerbation, keeping active and how to best maintain their home environment so as to minimise risk of exacerbation. In a randomised controlled trial patients did not experience any reduction in exacerbation frequency if they received the weather alert. However the trial did demonstrate that patients had surprisingly positive responses to the alerts and were able to use innovative new hand-held technology-based devices to assess their disease control. Further studies of this methodology and weather warnings are merited. A group from Lancashire also utilised a telephone-based weather warning alert system and used historical controls to see if an alert made any difference to exacerbation rates and hospital admissions.3 Significant reductions in out of hours’ visits were reported but there was no reduction in exacerbation rate of hospital admissions. The project was thought not to be cost-effective as overall costs per patient actually increased. Analysis of cost and cost/benefit are going to be essential components when looking at any change of service provision. Perhaps the most comprehensive approach to the management of a population of COPD patients is to case manage them. The Aintree group from Liverpool performed a prospective randomised controlled trial of case management for a 12 month period.4 Patients who had been admitted to hospital with an exacerbation were invited to take part. The intervention group had access to a 7 day a week help line, 5 day a week

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

healthcare worker review, hospital and home visits and an education programme. Clearly an enormous amount of effort was put into this study and the results were startling. Case management did not reduce exacerbation rate and was not cost-effective. This study highlights the need to perform high quality randomised, controlled studies of all healthcare interventions and not just drug studies. We must not base changes to resource provision on what we think ‘might’ or ‘should work but should be based on good quality evidence and must be cost-effective. Finally, new data is emerging as to which bacteria are being cultured in patients admitted with COPD exacerbations. Previous data have suggested a preponderance of H. influenzae, M. catarrhalis and of course S. pneumoniae. Data presented from James Cook Hospital5 suggested a change to this historical pattern and the audience in general tended to agree. The researchers demonstrated an increase in H. influenzae and S. pneumoniae but also a significant increase in the amount of Pseudomonas and E. coli seen. Further analysis and discussion led to the conclusion that the increase in Pseudomonas is probably representative of an increase in lung damage and airways that chronically do not clear sputum well. Moreover the role of S.pneumoniae must not be underplayed as this organism is very sensitive and difficult to culture and is thus underreported. Ignore Pneumococcus at your peril, but perhaps try and avoid the grandchildren who harbour most known respiratory viruses! So, do we know more? Yes we do, but perhaps we did not get the answers that we were expecting or wanted. We must all endeavour to practice evidence-based medicine in every aspect of our work and apply this to all parts of care provision. References are available on request.

Publisher: Peter Mas-Mollinedo peter@icr-uk.com Editor: Karen O’Malley, MPSI karen@icr-uk.com

Advertising Manager: 01932 342552 Oliver Webb oliverwebb1@mac.com Media & Projects Manager: Claire Payne claire@icr-uk.com Publications Manager: 01932 343098 Annie Wheeler annie@projectoverload.me.uk

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

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Diabetes UK - by Maria Dalby Reporting from the Diabetes UK APC, Liverpool

Options for therapy after metformin

ational and international guidelines for the management of newlydiagnosed Type 2 diabetes recommend metformin as first-line therapy in patients where lifestyle intervention alone is not sufficient to achieve glycaemic targets.1 However, a large proportion of patients remain uncontrolled on metformin alone and require additional therapy. In a plenary session at the Diabetes UK 2010 APC, four speakers outlined the supporting evidence for the major therapeutic options: sulphonylureas, glitazones, incretin-based therapy and insulin.

Sulphonylureas The case for sulphonylureas was made by Professor Cliff Bailey from Aston University in Birmingham. Sulphonylureas act directly on the pancreatic beta cells to stimulate insulin secretion even at low plasma glucose levels. In terms of clinical efficacy, add-on therapy with glibenclamide to metformin has been shown to improve glycaemic control over treatment with either agent alone.2,3 However, the ADOPT trial showed that the clinical efficacy of glibenclamide was less durable than that of metformin: after five years of treatment, glibenclamide was associated with a monotherapy faliure rate of 34%, compared with 21% with metformin and 15% with rosiglitazone.4 Whilst sulphonylureas tend to be less expensive to prescribe compared with newer agents, and have the advantage of extensive experience and safety documentation, their use may be limited by their contraindication profile which includes other antidiabetic agents, warfarin and beta blockers for the treatment of hypertension.

Glitazones The glitazone class of oral antidiabetic agents was presented by Professor Roy Taylor of Newcastle University. The NICE guidelines recommend adding a glitazone for patients who fail to achieve their glycaemic targets despite treatment with metformin and sulphonylureas.1 In addition to their proven clinical efficacy, the glitazones appear to have a particularly advantageous mechanism of action as the extent of insulin-mediated suppression of glucose production in the liver has been shown to be inversely correlated with the amount of triglycerides in the liver an effect which is inhibited by coadministration of fibrates.5 In addition, data from the US Diabetes Prevention Program (DPP) show that troglitazone was capable of delaying the onset of Type 2 diabetes in high-

Full reports from the Diabetes UK APC can be found on

a request-only electronic journal. Please email: subscriptions@icr-uk.com and mark your email ‘Diabetes.MED’

risk individuals.6 However, in clinical practice the use of glitazone agents will be limited by some of their less than acceptable side effects - most importantly weight gain, but the risk of fluid retention and maculopathy, fractures and anaemia must also be considered in at-risk individuals.

Incretin-based therapy Professor David Matthews of the Oxford Centre for Diabetes, Endocrinology and Metabolism presented the so-called incretinbased therapeutic class. This class comprises agents that act directly via a glucagon-like peptide 1-mediated pathway (GLP-1 agonists), including exenatide and liraglutide, and agents that act by protecting native GLP-1 from inactivation by dipeptidyl peptidase-4 (DPP-4) such as sitagliptin and vildagliptin. The GLP-1 agonists are administered by subcutaneous injection and have been shown to be as effective as the oral antidiabetic classes and insulin for controlling hyperglycaemia,7-11 but with the added benefit of substantial weight loss7,8 and loss of visceral fat.12 The DPP-4 inhibitors are administered orally and have been shown to be superior to GLP-1 agonists for controlling postCONTINUED ON PAGE 6 >

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Diabetes UK - by Maria Dalby Reporting from the Diabetes UK APC, Liverpool

Incidence trends in childhood diabetes Dr. Chris Patterson, Centre for Public Health, Queen’s University Belfast

he incidence of Type 1 diabetes in children younger than 15 years has risen steadily over the last 20 years, and continues to increase. Incidence data from EURODIAB, a large population-based registry study in 17 European countries, show that if the present trends continue, the number of new children diagnosed with Type 1 diabetes will double from 2005 to 2020 in the age group younger than five years, and prevalent cases younger than 15 years will rise by 70%. Dr. Chris Patterson from Belfast has been one of the principal investigators on EURODIAB; in his talk at the Diabetes UK 2010 APC he outlined the key findings from the study and some

recent meta-analysis data that has a bearing on the subject. The EURODIAB dataset consists of 29,311 newly diagnosed children aged <15 years with Type 1 diabetes, registered during the period 1989-2003. The overall annual increase in incidence was 3.9% (95% CI 3.6, 4.2), with the greatest increase seen in the age group 0 to 4 years (5.4%; 95% CI 4.8, 6.1). The number of new cases in Europe in 2005 is estimated as 15,000; in 2020, the predicted number of new cases is 24,400, with a doubling in numbers in children younger than 5 years. Prevalence under age 15 years is predicted to rise from 94,000 in 2005 to 160,000 in 2020.1 Several factors have been proposed for

explaining this increase. A recent pooled analysis of 30 longitudinal studies showed a 5% (95% CI 2%, 9%) increase in childhood Type 1 diabetes odds per five-year increase in maternal age (p=0.006); however, there was heterogeneity (I2=70%) among the pooled studies. The authors concluded that a very small percentage of the recently observed increase in the incidence of childhood Type 1 diabetes may be explained by increasing numbers of older mothers, which in turn may be linked with factors such as increased exposure to infections or toxins, or increased maturation of the immune system.2 There has also been data published that show that children weighing more than 4kg at birth have a 10% higher risk of developing diabetes compared with smaller children, which could be explained by the fact that birth weight is a potential marker of maternal nutrition, body weight or illness, or alternatively by episodes of hyperglycaemia.3,4 In addition, children delivered by caesarean section have been shown to have a 20% higher risk of developing Type 1 diabetes, possibly due to factors such as an altered gut micro flora or episodes of pregnancy hyperglycaemia.5 However, Dr. Patterson pointed out that the perinatal associations studied to date have been comparatively weak, and most likely caused by unknown confounding factors, and that even taken together these factors cannot account for more than a small proportion of the increase in Type 1 diabetes. References available on request

< CONTINUED FROM PAGE 5

prandial plasma glucose levels.13 A recent addition to the NICE guidelines for Type 2 diabetes recommends addition of a GLP-1 agonist as third line treatment after metformin and sulfonylurea in patients with BMI over 35 or unable to tolerate insulin, and a DPP-4 inhibitor as second-line treatment instead of sulfonylurea in patients with high risk of hypoglycaemia.14

Insulin In the concluding presentation, Professor Melanie Davies from the University of

Leicester gave an overview of insulin and its place in Type 2 diabetes therapy. Patients often have concerns about starting insulin therapy and may regard it as a failure; however, Professor Davies reminded the audience that insulin is the most potent glucose-lowering therapy available and has no upper dose limit. Data from a study in which patients began insulin therapy at an early stage of their diabetes and were then followed up for 10 years, showed significant benefits in favour of early insulin over conventional therapy with respect to microvascular disease (24%, p=0.001),

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

myocardial infarction (15%, p=0.01), death from any cause (13%, p=0.007), and all diabetes-related endpoints (9%, p=0.04) [15]. In addition, there have been reports of links between early proactive insulin use and lasting improvements in beta cell function16,17 which may be mediated by an antiinflammatory effect via suppression of nuclear factor kappa B.18,19 The recommended strategy for initiating insulin therapy is to start with basal insulin and intensify treatment as indicated by the HbA1c response.20 References available on request

Early ACTID trial of diet and exercise in newly diagnosed patients Dr. Rob Andrews, University of Bristol

iet and exercise are mainstay interventions for newly diagnosed Type 2 diabetes; national and international guidelines recommend that lifestyle changes and weight loss should be attempted before any medication other than metformin is prescribed. However, the supporting evidence is far from clear cut; some studies have reported only minor treatment effects of diet and exercise regimens in newly diagnosed patients.1,2 The Early ACTivity In Diabetes (Early ACTID) trial was designed to establish the size of any beneficial effect of increased physical activity on factors such as glycaemic control,

blood pressure, serum lipid profiles and insulin resistance compared with control regimens involving diet alone and standard care, respectively. The results were reported at the Diabetes UK APC by Dr. Rob Andrews from the University of Bristol. The Early ACTID trial was designed as a randomised controlled study, with the investigators blinded to the regimen allocation. To be eligible for inclusion, patients must be aged <80 years and have had a diagnosis of Type 2 diabetes for 5-8 months, and also have a body mass index (BMI) over 25. The diet intervention was based on the Balance of Good Health model3 and dietary guidelines issued by

Diabetes UK4 and aimed to achieve a 5% weight loss during the course of the study. The exercise intervention included the same dietary regimen as the diet-alone arm, with the addition of 30 minutes of walking daily on five days per week. The primary efficacy outcome was the change in HbA1c and blood pressure at six and 12 months of treatment. After six months of treatment, statistically significant reductions in HbA1c and blood pressure were seen both in the diet and exercise and diet-alone arms, compared with patients given standard care. These reductions were CONTINUED ON PAGE 8 >

Break through the glycaemic barrier with control that lasts

actos

pioglitazone HCl

Durable glycaemic control For your Type 2 diabetes patients uncontrolled on metformin alone, break through with Actos to give them the durable glycaemic control they need

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

Legal status: POM. Further information available from: Takeda UK Ltd. Takeda House, Mercury Park, Wycombe Lane, Wooburn Green, High Wycombe, Bucks HP10 0HH.

Date of preparation November 2009. AC091159m

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Diabetes UK - by Maria Dalby Reporting from the Diabetes UK APC, Liverpool

Erectile dysfunction: Its link with cardiovascular disease and diabetes Dr Graham Jackson, Department of Cardiology, Guy's & St Thomas' Hospital, London

rectile dysfunction (ED) is common in diabetes1-4 – more common, in fact, than in both hypertension5,6 and coronary artery disease (CAD).7-12 Although ED has a dramatic effect on the diabetic patient’s quality of life, men are often reluctant to discuss the subject with their doctors due to embarrassment and stigma.13 However, what is less widely known is that ED may be a warning sign of cardiovascular complications in Type 2 diabetes and could provide a window of opportunity for reducing long-term cardiovascular morbidity in these patients if detected at a sufficiently early stage. Dr. Graham Jackson reviewed the supporting evidence and discussed data in a clinical context. Several pathogenic mechanisms contribute to the development of ED in men with diabetes. Both macro- and microangiopathy is involved, as well as polyneuropathy of penile and pelvic nerves which control not only erection but also emission and ejaculation.14 Diabetes has been shown to constitute a significant risk factor for developing ED even after adjusting for age and cardiovascular co-morbidity.15 The likely mechanism for this increased risk is the observed close correlation between the metabolic syndrome and Type 2 diabetes on the

< CONTINUED FROM PAGE 7

maintained at 12 months. No significant difference was seen between the diet and exercise and diet-alone arms at any time point. In addition, patients in the diet and exercise and diet-alone arms were less inclined to begin antidiabetic drugs compared with patients on standard care. Both intervention groups showed significant reductions in serum triglycerides and insulin resistance as assessed by the Homeostatic Model Assessment (HOMA); in addition, patients in the diet and exercise arm

one hand and low serum testosterone levels on the other hand. Treatment guidelines issued jointly by the International Society for the Study of the Aging Male (ISSAM), the International Society of Andrology (ISA), the European Association of Urology (EAU) and the American

‘

Several pathogenic

mechanisms contribute to the development of ED in men

’

with diabetes.

Urological Association (AUA) recommend that serum testosterone levels should be monitored in men with Type 2 diabetes with symptoms suggestive of testosterone deficiency.16 There is a strong rationale for clinicians to actively investigate sexual problems in diabetic men, not only because of the impact on the patient’s quality of life, but because ED has been shown to predict silent CAD in patients with otherwise uncomplicated Type 2

significantly increased their HDL levels compared with the diet alone and standard care arms. Blood pressure and the use of antihypertensive medications remained largely unchanged during the course of the study. No significant difference was seen in the proportion of patients who achieved a 5% weight loss. The investigators speculated that there may have been differences in the way patients in the diet and exercise and diet-alone arms were treated, despite the blinding of investigators to the regimen allocation. It is also possible that the patients allocated to diet and exercise may

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

diabetes.17 ED has been shown to be three times stronger than smoking for predicting asymptomatic myocardial infarction - when comparing with microalbuminuria and dyslipidaemia, the predicting power of ED was up to five times greater. The reason why ED appears long before any other vascular disease is primarily the small diameter of the cavernosal arteries, arteries, and also the fact that compared to other organs in the body, the penis is a highly vascular organ with a high content of endothelium and smooth muscle per gram tissue, and thus sensitive to changes in oxidative stress and systemic NO levels.18 A prospective study involving 1,655 men aged 40 to 70 years who were followed up for 15 years showed that ED was associated with a hazard ratio of 1.26 for all-cause mortality and 1.43 for cardiovascular mortality. A retrospective study in 1,660 men over 10-15 years showed that the rate of cardiovascular events doubled in men with ED (relative risk 2.2) and in the age group under 40 years the increase was seven-fold (p<0.0001). Dr. Jackson concluded by stressing the importance of early detection of ED and a multi-disciplinary approach to capture at-risk patients at an early stage and seize the opportunity to reduce the overall risk. References available on request

have chosen a somewhat different diet to those in the diet alone arm, which may account for the lack of difference between the two groups. Despite these question marks, the Early ACTID trial showed that it is feasible to achieve and maintain increased physical activity levels in Type 2 diabetes patients for a prolonged period of time, and that there appears to be additional beneficial effect of exercise compared with diet alone although no independent effect on HbA1c and blood pressure was observed. References available on request

Psychiatry Report

More evidence of marijuana-psychosis link

oung adults who reported a longer duration since first exposure to marijuana had a two to four-fold greater prevalence of three different psychosis-related outcomes, John McGrath, MD, PhD, of the Queensland Centre for Mental Health Research in Wacol, and colleagues concluded in an article published online in Archives of General Psychiatry. A similar association was observed in a subset of sibling pairs. "Apart from the implications for policymakers and health planners, we hope our findings will encourage further clinical and animal model-based research to unravel the mechanisms linking cannabis use and psychosis," the researchers concluded. Several prospective-cohort studies have demonstrated an association between early marijuana use and an increased risk of psychosis. On the basis of such studies, reviews of the issue have generally concluded that early use of marijuana, or cannabis, is a modifiable risk factor for psychosis-related outcomes, the authors wrote.

However, some concern has persisted about potential methodologic biases and unmeasured confounders in the cohort studies. In an effort to address the concern, McGrath and colleagues examined the association between cannabis use and psychosis in 3,800 participants in a long-term evaluation of pregnancy and outcomes. In contrast to prior cohort studies, the authors incorporated a subset analysis involving 228 sibling pairs. "If a significant association between cannabis use and psychosis-related outcomes was not detected in sibling pairs, it would seriously weaken the argument that cannabis use was a risk-modifying factor for psychosis-related outcomes," they wrote. Participants were born between 1981 and 1984 at a single hospital in Brisbane. Mothers and their offspring were followed up at five, 14, and 21 years after birth. At the 21-year followup, McGrath and colleagues retrospectively assessed cannabis use among the offspring, whose age averaged 20 and ranged from 18 to 23. Cannabis use was assessed by means of the young adults' responses to two questions: In the last month, how often did you use cannabis, marijuana, pot, etc.? At what age did you first use cannabis? Possible responses to the first question were never, every day, every few days, once or so, and not in the past month. Investigators separated the cohort into four groups on the basis of self-reported cannabis use. One group included never-users, and the remaining three groups were categorised by duration since first use of cannabis: three years or less, four to five years, six years or more. Investigators compared participants' history of cannabis use with three psychosis-related outcomes: non-affective psychosis, hallucinations (assessed by the Computerised International Diagnostic Interview), and the Peters et al Delusions Inventory (PDI) score (Schizophr Bull 2004; 30: 1005-1022). The authors

found that 65 participants met criteria for a diagnosis of non-affective psychosis, and 233 reported at least one hallucination-related incident. The PDI has a score range of 0-21, and participants were grouped into PDI quartiles representing scores of ≤2, 3 or 4, 5 to 7, and ≥8. The authors analysed the results by means of two statistical models, one adjusted for participant sex and age at testing and the other adjusted for sex, age at testing, presence of hallucinations at the 14-year follow-up, and parental history of mental illness. Using neverusers as the reference, the odds ratio for nonaffective psychosis increased from 1.5 to 2.1 or 2.2 in the two models as duration of first cannabis use increased. The odds for hallucinations increased from 1.4 to 2.5 and 1.5 to 2.8. Comparing the lowest and highest quartiles of PDI scores, the authors found that the odds of a higher score increased from 1.6 to 4.0 or 4.3 as duration since first cannabis use increased. Associations for all three psychosis-related outcomes were statistically significant in both models (P=0.001 to P<0.001). The sibling analysis was limited to the PDI scores. For each pair, the authors calculated difference scores for duration since first cannabis use and PDI total score. The association between time since first cannabis use and PDI score remained statistically significant in the sibling subset analysis. Limitations of the study included: retrospective self-reporting of time since first cannabis use, lack of data on cumulative exposure to cannabis, no clinical validation of nonaffective psychosis diagnosis and lack of use of the instrument at the 14-year follow-up, and loss of participants at the 21-year mark with significant differences in the group lost to follow-up compared with those retained. Disclosure: The study was supported by the National Health and Medical Research Council of Australia. The authors had no disclosures. Reference: 1. McGrath J, et al "Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults" Arch Gen Psych 2010; DOI: 10.1001/archgenpsychiatry.2010.6.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Psychiatry Report

Greater sense of purpose associated with substantially reduced risk of Alzheimer's disease

atients who maintain a greater sense of purpose in life as they age may have greater protection against Alzheimer's disease, researchers have found. Those with a purpose had more than a 50% reduced risk of the disease (HR 0.48, 95% CI 0.33 to 0.69, P<0.001), Patricia A. Boyle, PhD, of Rush University Medical Centre in Chicago, and colleagues reported in the recent Archives of General Psychiatry. "The tendency to derive meaning from life's experiences and to possess a sense of intentionality and goal directedness are associated with a substantially reduced risk of Alzheimer's disease and a less rapid rate of cognitive decline in older age," the researchers

wrote. Some data have suggested that psychological factors such as extraversion and neuroticism, as well as experiential factors including social networks, are associated with risk of Alzheimer's disease. Purpose which the researchers define as a "psychological tendency to derive meaning from life's experiences and to possess a sense of intentionality and goal directedness that guides behaviour" has long been hypothesised to protect against adverse health outcomes. For example, it was recently reported to be associated with longevity, they noted. But there was little information on the association of purpose with Alzheimer's disease. So the researchers conducted a prospective,

longitudinal study of 951 community-dwelling older patients without dementia who participated in the Rush Memory and Ageing Project. At baseline, the mean age of the participants was 80.4 years. Each had a baseline evaluation about purpose in life, which incorporated a 10-item scale that included agree/don't-agree statements such as "I feel good when I think of what I have done in the past and what I hope to do in the future" and "I enjoy making plans for the future and working them to a reality." Patients were followed for up to seven years, with a mean follow-up of about four years. During that time, 155 patients developed Alzheimer's disease. The researchers found that

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EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

those who developed the disease were older and reported lower purpose in life than those who did not. Greater purpose in life was associated with a substantially reduced risk of disease (HR 0.48, 95% CI 0.33 to 0.69, P<0.001). And a person with a high score on the purpose in life measurement was 2.4 times more likely to remain disease- free than a low-scorer. The association persisted after controlling for several factors, including depressive symptoms, neuroticism, social network size, and number of chronic medical conditions, the researchers found. (HR 0.60, 95% CI 0.39 to 0.92, P=0.02). Similarly, those who developed mild cognitive impairment (MCI) were older and reported lower purpose in life scores. They also had a higher number of depressive symptoms. Having a greater sense of purpose was associated with reduced MCI risk of almost 30% (HR 0.71, 95% CI 0.53 to 0.95, P=0.02), as well as a 1.5-fold increased likelihood of remaining MCI-free, compared with someone

with a low score. These patients also had a significantly slower rate of cognitive decline, the researchers reported (P<0.01). They said they are unsure of the biological mechanisms involved in the association, but other studies have found sense of purpose to be negatively associated with immune markers, including cortisol and inflammatory cytokines. Sense of purpose also been positively associated with high-density lipoprotein (HDL), or "good," cholesterol, and negatively correlated with waist-hip ratios. The findings may have important public health implications, the researchers added, as they potentially provide a new treatment target for interventions aimed at enhancing health and well-being in older adults. "Purpose in life is a potentially modifiable factor that may be increased via specific behavioural strategies that can help older persons identify personally meaningful activities and engage in goal-directed behaviours," they wrote. "Even small

behavioural modifications ultimately may translate into an increased sense of intentionality, usefulness, and relevance." Among the limitations of the study, the authors said, were possibly limited generalisability, and inability to determine causation. In addition they noted that "there are factors that we did not measure (e.g., apathy, motivation, and spirituality or religiosity) that may affect the associations of purpose in life with health outcome." Disclosure: The study was supported by grants from the National Institute on Aging, the Illinois Department of Public Health, and the Robert C. Borwell Endowment Fund. The researchers reported no conflicts of interest. Reference: 1. Boyle PA, et al. Effect of a purpose in life on risk of incident Alzheimer disease and mild cognitive impairment in community-dwelling older persons. Arch Gen Psychiatry 2010; 67(3); 304-10.

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Psychiatry Report

Broad application of bipolar diagnosis in children may do more harm than good Researchers critique expanded diagnosis and recommend strategies for dealing with troubled children

roubled children diagnosed with bipolar disorder may fare better with a different diagnosis, according to researchers at The Hastings Centre. The researchers support an emerging approach, which gives many of those children a new diagnosis called Severe Mood Dysregulation (SMD) or Temper Dysregulation Disorder with Dysphoria (TDD). The findings come soon after proposed revisions to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) were opened to public comment. In a paper published in Child and Adolescent Psychiatry and Mental Health, Erik Parens and Josephine Johnston examine the evolution of the diagnosis of bipolar disorder in children and its dramatic increase since the mid 1990s, after the criteria for diagnosis broadened. They

emphasise that there is vigorous debate in paediatric psychiatry about whether symptoms in children accurately reflect the criteria for bipolar disorder, particularly for mania. The increase in cases has led to concerns about accurately defining psychiatric disorders in children as well as the safety and efficacy of resulting pharmacological treatment. It is difficult to diagnose psychiatric disorders in children, Parens and Johnston write, and many children receiving bipolar diagnoses exhibit behaviours that do not closely fit the disease's criteria. "Using new labels such as SMD or TDD reflects that physicians do not yet know exactly what is wrong with these children or how to treat it," said Johnston. "Facing up to this uncertainty could lead to better treatment recommendations and more accurate longterm prognosis." A new diagnostic category would also help reframe the research agenda. Their findings come from an interdisciplinary series of workshops funded by a grant from the National Institute of Mental Health. Participants included psychiatrists, paediatricians, educators, bioethicists, parents, and social scientists. Erik Parens is a senior research scholar and Josephine Johnston a research scholar at The Hastings Centre, a bioethics research institution. Among the workshop conclusions: • The bipolar label may fit poorly many of the children who have received it over

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

the last decade. • There is debate about what children's symptoms represent. For example, what is characterised as mania in children is very different from its features in adults. Mania is a hallmark feature of bipolar disorder, formerly known as manic-depressive disorder. • The bipolar label, which has a strong genetic component, can distract from addressing the family or social context. • Physicians must be forthcoming with families about uncertainties and complexities in the diagnosis and treatment of bipolar disorder in children. • Current training practices and reimbursement policies may leave some psychiatrists and paediatricians unable to deliver the comprehensive care that these children need. The authors also note that, while experts sometimes disagree about labels, the workshop group universally agreed that "children and families can suffer terribly as a result of serious disturbances in children's moods and behaviours," and that these troubled children desperately need help. They also write, "It is a deeply regrettable feature of our current mental health and educational systems that some DSM diagnoses are better than others at getting children and families access to [needed] care and services." The Hastings Centre is a nonpartisan bioethics research institution dedicated to bioethics and the public interest since 1969. The Centre is a pioneer in collaborative interdisciplinary research and dialogue on the ethical and social impact of advances in health care and the life sciences. The Centre draws on a worldwide network of experts to frame and examine issues that inform professional practice, public conversation, and social policy. Learn more about The Hastings Centre at: www.thehastingscenter.org For further information contact: Michael Turton turtonm@thehastingscenter.org

High-dose donepezil slows symptom progression in advanced Alzheimer's disease

ccording to the data presented at the 25th Conference of Alzheimer's Disease International (ADI), patients with advanced Alzheimer's disease (AD) and dementia were observed to have stronger symptom improvement with a higher dose of donepezil. Patients (mean age, 78.4 years) also demonstrated significantly increased cerebral blood flow following dose increase. The current treatment for patients with advanced AD and dementia in Japan is donepezil 5mg. For the study, Kinoshi Kanaya, MD, Department of Geriatric Medicine, Tokyo Medical University, and Hachioji Medical

Centre, Tokyo, Japan, and colleagues assessed the efficacy of donepezil 10mg daily in patients whose symptoms of dementia were progressing with donepezil 5mg. Of the 24 patients available for analysis, 31.2% demonstrated increased cognitive function assessed by the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive subscale and 31.5% showed no change (no deterioration) in cognitive function. An increase in symptoms was seen in 31.3% (P = .05) of treated patients. The researchers also administered technetium -99m-ethyl cysteinate diethyl ester single photon emission computed tomography imaging twice

after administration of donepezil 10mg. A total of 20 patients (83.3%) demonstrated increased cerebral blood flow specifically in the bilateral temporal, occipital, and parietal lobes (P = .05). One patient was withdrawn from the study due to adverse effects involving gastrointestinal symptoms. However, the treatment was generally well tolerated. Presentation title: Usefulness of Administration of 10mg/Day Dosage Donepezil Hydrochloride (Aricept) to Dementia Alzheimer's Type (DAT) - Comparative Study With 5mg By Neuropsychological Testing and SPECT Imaging. Abstract P002

Sertraline plus naltrexone keep depressed alcoholics dry

hen added to cognitive behavioural therapy, 53.7% of alcoholic and depressed patients taking the two drugs achieved abstinence for a median of 98 days, compared with rates of 21.3% to 27.5% and median durations of less than a month for either drug alone or placebo (P=0.001), reported Helen M. Pettinati, PhD, of the University of Pennsylvania in Philadelphia, and colleagues. Writing online in the American Journal of Psychiatry, the researchers indicated that depression and alcohol dependence frequently occur together and is particularly difficult to treat. "The present findings suggest that patients with both disorders would benefit from combination treatment with an antidepressant and medication for alcohol dependence," they wrote. The study enrolled 170 patients with both depression, defined as a

Hamilton Depression Rating Scale score of at least 10, and alcohol dependence meeting DSM-IV criteria. Patients were excluded if they had other substance dependence issues except for tobacco, or if they had other mental illnesses other than depression. As a result of these exclusions, only about half of patients screened were accepted into the study. All patients received weekly sessions of cognitive behavioural therapy. They were randomised to receive one of the following treatment regimens for 14 weeks: double placebo, sertraline at 200 mg/day plus placebo, naltrexone at 100 mg/day plus placebo, or both drugs at those doses. The main outcome measures for alcohol dependence were the percentage of patients totally abstinent during treatment and the median and mean time to resume heavy drinking. Oddly, the mean duration of abstinence in the combined-drug patients was much shorter than the median,

64 days (SD 40.8) versus 98 days. For the other treatment groups, the means were ranged from 40 to 45 days, almost double the medians. The combination regimen was also more effective than the other treatments against depression. The mean Hamilton score after treatment was 6.9, with 83.3% of patients no longer clinically depressed. In the other treatment arms, mean Hamilton scores were higher (8.0 to 11.7, P=0.04 relative to the combination) and fewer patients achieved clinical remission (48.1% to 68.8%). Sertraline monotherapy actually was the least effective among the four treatments in relieving symptoms of depression, although the difference from double placebo and naltrexone monotherapy was not large. As with most treatments for alcoholism, treatment failures were common. From 41% to 48% of each CONTINUED ON PAGE 14 >

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Psychiatry Report

Antidepressants beneficial in physically ill patients

ntidepressants are effective against depression in patients suffering from physical illnesses, according to a new systematic review by Cochrane researchers at King's Health Partners Academic Health Sciences Centre in the UK. The researchers found the drugs were more effective than placebos at treating depression in these patients. One of the most neglected areas of healthcare research is the effects of physical illness on an individual's mental health. Research suggests that more than ten percent of patients suffering from physical diseases also suffer from depression. For reasons that are not entirely clear, depression may amplify the symptoms of physical disease and increase the risk of these patients dying. Studies suggest that doctors are less likely to prescribe antidepressants to people who are physically ill because they are unsure if they are helpful for these patients. Therefore, it is important to know whether antidepressants can be effective in people with physical illness. The review included 51 studies comparing

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group failed to complete the 14-week regimen. Adverse events were the most common reason in the combination-drug group (seven of 18 dropouts), whereas clinical deterioration was most common with double placebo and drug monotherapy. Nevertheless, after 90 days, about 43% of patients in the combination group were abstinent, compared with 12% to 21% of patients in the other groups. About 54% of combination-group patients did not have a heavy drinking day within the first 90 days after starting treatment, compared with about 30% in each of the other groups. Adverse events were common and many were rated as severe or very severe, including anxiety and irritability (29% of patients), fatigue (25%), sexual dysfunction (29%), and headache (14%). Ashwin Patkar, MD, of Duke University in Durham, N.C., who was not involved with the study, told MedPage Today that the study had a "good take-home message for physicians in

antidepressants to placebos. Most studies trialed selective serotonin reuptake inhibitors or tricyclic antidepressants. A total of 3603 patients were involved, suffering from physical illnesses including stroke, HIV/AIDS, Parkinson's disease and cancer. The researchers found that antidepressants were more effective than placebos, although patients receiving antidepressants were more likely to experience adverse effects, including sexual dysfunction and dry mouth. For every six people receiving treatment, one more could be expected to benefit at between six and eight weeks if they were taking antidepressants. Lead author Lauren Rayner of King's College London said, "Although trials were small, they do seem to indicate a genuine benefit associated with antidepressants. However, patients with more severe physical illness and more severely depressed patients were not included in the trials. It is possible that those with more severe illness don't respond so well to treatment with antidepressants. This is something that should be addressed in further studies." Senior investigator Professor Matthew

Hotopf, Institute of Psychiatry, King's College London added: "As a clinician I see many patients struggling with the effects of physical disease on their mental health. Doctors should take into account patients' preferences, symptoms and possible interactions with any other medications they are taking when prescribing antidepressants to physically ill patients". He concludes: "This is a critical area of research which will help doctors maximise a patient's treatment and recovery from the mental and physical symptoms of illness." "This research is very important for millions of patients and families who are experiencing physical illness, including the most advanced stages of disease," said Professor Irene Higginson, senior investigator and Head of the Cicely Saunders Institute, King's College London. "Until now many doctors and nurses were worried that these treatments did not work well in people with physical illness. This result shows that they are usually of benefit. Already we are using the results to inform a new European Guideline for doctors and nurses on the management of depression."

terms of how they can use medications and combine them with behavioural therapy for alcohol dependence." But Patkar, who has contributed a commentary on the study published in the journal, also cautioned that clinicians in ordinary practice may not experience the same level of results reported in the study. The researchers excluded many patients with common comorbidities that might reduce the effectiveness of treatment, he noted. He also pointed to the relatively high adherence to treatment in the study, 87% for medications across the entire sample, and 59% for the weekly therapy sessions, indicating it was both a strength and a limitation of the study. Patkar said treatment compliance in ordinary practice is not usually that good. It's typically higher in clinical trials because of the supervision and encouragement that participants receive. But he added that it's not impossible for clinicians to fill that role or enlist others to help. "They can encourage that kind of supervision and adherence in their patients and get good

outcomes," he said. In treating his own patients, Patkar said, "I make sure there is a member of the family who is involved with the care, and who actually becomes almost a part of the treatment team - supervising medications, supervising visits, and reporting to us what is going on."

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Disclosure: The study was supported by the National Institute on Alcohol Abuse and Alcoholism and Pfizer, which supplied sertraline and matching placebo. Study authors reported relationships with Alkermes, Eli Lilly, Merck, GlaxoSmithKline, Lundbeck, Abbott, and Ernbera Neurotherapeutics. Patkar has had relationships with AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, McNeil Consumer and Specialty, Organon, Orphan Medical, Titan, Pfizer, Reckitt Benckiser, Cephalon, Jazz, and Lundbeck. Reference: Pettinati H, et al. A Double-Blind, Placebo-Controlled Trial Combining Sertraline and Naltrexone for Treating CoOccurring Depression and Alcohol Dependence. Am J Psychiatry 2010; DOI:10.1176/appi.ajp.2009.08060852.

American Academy of Allergy, Asthma and Immunology - by Peter Mas-Mollinedo Reporting from the AAAAI, New Orleans

Stepping up therapy improves asthma in children

hildren with asthma who continue to have symptoms while using low-dose inhaled corticosteroids (ICS) can benefit from "stepping up" treatment by increasing the dosage or adding either a long-acting beta agonist (LABA) or a leukotriene-receptor antagonist (LTRA), according to a new triple-crossover randomised study called BADGER (Best Add-On Therapy Giving Effective Responses). In fact, 98% of the study participants showed a significant improvement in asthma control after the addition of at least 1 of these options, according to research presented here at the American Academy of Allergy, Asthma and Immunology (AAAAI) 2010 Annual Meeting and published online simultaneously in The New England Journal of Medicine. Although the overall best response was achieved by adding a LABA, many of the children had a best response with one of the other step-up treatments, "highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy," lead author and principle investigator at the lead centre, Robert F. Lemanske Jr, MD, professor and head of the Division of Pediatric Allergy, Immunology, and Rheumatology at the

University of Wisconsin in Madison, told meeting attendees. He added that factors such as baseline Asthma Control Test (ACT) score, the absence of eczema, and race might also help clinicians to "better predict which of the three treatment options will help a patient the most." Although clinicians usually agree on treatments going from step 1 (intermittent asthma) to step 2 (persistent), the few studies that have been conducted on how to best treat children whose asthma is poorly controlled while receiving low-dose ICS have shown inconsistent results, reported Dr. Lemanske. Researchers from five centres (in four states), making up the National Heart, Lung, and Blood Institute-funded Childhood Asthma Research and Education Network, worked on the BADGER trial. They sought to conduct a comparison study to establish not only which step-up therapy was best, but also "whether there are phenotypic or genotypic characteristics that can be used to predict whether a child will have a better response to one particular treatment than to another." A total of 498 children between the ages of 6 and 17 years with mild to moderate asthma were enrolled between March 2007 and July 2008, with 157 (65.4% male; mean age, 10.8 years) receiving each of the 3 step-up

treatments in random order for 16 weeks each. These treatments were the standard low-dose ICS (100µg of fluticasone twice daily) plus either the LABA salmeterol (50µg twice daily) or the LTRA montelukast (5 or 10mg daily), or 2.5 times the standard ICS dose (250µg fluticasone twice daily) only. Each patient also received a metered-dose inhaler of albuterol and prednisone. At the end of each 16-week period, the number of days that the asthma symptoms were under control, lung function, and the number of exacerbations and attacks were measured before the patient moved on to the next treatment option.

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The absence of eczema,

and race might also help clinicians to better

predict which of the three treatment options will

’

help a patient the most.

Methods used included the Paediatric Asthma Quality of Life Questionnaire, the ACT (with scores from 0 to 27), spirometry tests, and patient- or guardian-recorded diary entries. The results, concentrating on the 165 patients who completed at least 2 study periods, showed that "although our goal was for 25% of the patients to see a difference in their asthma symptoms after using at least 1 of the treatments, we were surprised to see that 161 showed substantial improvement [P < 0.001]," said Dr. Lemanske. The best response was shown in almost 40% of the patients by adding the LABA, in 30% by adding the LTRA, and in 28% by increasing the dose of ICS. Using rank-ordered logistic regression, the predicted response to the LABA addition was significantly better than to the addition of the LTRA (relative probability [RP], 1.6; 95%

CONTINUED ON PAGE 17 >

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

COPD. Think again COPD is more than just an airway disease. The progressive nature of COPD is associated with chronic inflammation, which is different to asthma inflammation and involves a different mix of inflammatory cells and mediators.1 Now that we have a better understanding of COPD, we have a fresh opportunity to investigate different approaches to treatment. Nycomed are committed to working with clinicians in research and development into the management of COPD, and to help you and your patients to think differently about COPD in the future.

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease (updated 2008). Available at www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=2003. UK/DA/09/067 Date of preparation: September 2009.

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American Academy of Allergy, Asthma and Immunology - by Peter Mas-Mollinedo Reporting from the AAAAI, New Orleans

Stepping up therapy improves asthma in children < CONTINUED FROM PAGE 15

confidence interval [CI], 1.1 - 2.3; P = 0.004) and the ICS step-up (RP, 1.7; 95% CI, 1.2 - 2.4; P = .002). "In other words, the LABA was more than one and a half times as likely to produce the best response," explained Dr. Lemanske. "All three therapies clearly have a place in the management of kids with persistent asthma not well controlled on low-dose [ICS] alone," said investigational team member Leonard B. Bacharier, MD, from the Department of Pediatrics at Washington University in St. Louis, Missouri, in a press release. "Statistically, LABA therapy was most likely to help the most patients, but it's hard to look at an individual patient and know which one to choose." Significant predictor factors included ACT score, eczema, and race. LABA treatment was the best add-on therapy for patients with an ACT score greater than 19 (P = .009). However, "if it was 19 or under, there was no difference among the therapies in producing a differential response," reported Dr. Bacharier. Although patients who had eczema did well on any of the three treatments, those who did not have eczema did better on the LABA. The LABA was also most likely to give the best response in whites. The LABA and higherdose ICS were equally likely to show the best response in African Americans, whereas the LTRA was least likely. Factors that were not found to be significantly predictive of a drug's effectiveness included age, sex, allergies, bronchodilator response or reversibility, and number of recent exacerbations. Dr. Lemanske said that although he was disappointed to not find more predictors, "we're not done analysing and still have lots of genotyping to do." "Overall, our findings suggest that there is a ceiling effect of low-dose [ICS] in many, though not all, children, and that the addition of a different class of medication is often required to

achieve improvements in asthma control," said Dr. Lemanske. "The important take-home message is that if you choose something at step 3 and you're not happy with it, based on the control, instead of pushing it up to step 4, look to one of these other treatments." He noted, however, that none of the study treatments provided perfect asthma control, and that there were still 120 asthma exacerbations or attacks among the patients who required rescue medication with prednisone. "We obviously still need to do more work."

‘

The important take-home message is

issues," said John Oppenheimer, MD, associate clinical professor of medicine at New Jersey Medical School in Newark, and past vice-chair of AAAAI's Clinical Therapeutics Committee. "It was great to see a real comparison study instead of one that just compared itself to placebo," said Dr. Oppenheimer, who was not involved with the study. "I think the future of medicine and asthma is in understanding phenotypes and, ultimately, understanding genotypes, and then using that information to help stratify the likelihood of having severe asthma and to help us pick what medicines are most appropriate." "This study begins to delve into possible phenotype differentiations, as well as the most appropriate intervention, when someone is on an ICS and not in control," he added. "Certainly the LABA add-on appeared to be the most likely improvement, but it wasn't the best for all patients. Practicing medicine has been likened to art, and I would say that this study reminds us that to be a better artist, you need to take a step back and make sure you're happy with your canvas." He noted that the predictive factors found will need to be replicated in larger studies, "but it's one step closer to helping us as physicians put our patients on the right medicine the first time."

that if you choose something at step 3 and you're not happy with it, based on the control, instead of pushing it up to step 4, look to one of

’

these other treatments. Dr. Lemanske

When asked about the recent mandates of the US Food and Drug Administration (FDA) on the need to lower the use of LABAs in patients with controlled asthma, Dr. Lemanske said that that was like comparing apples and oranges. "The FDA was talking about step-down treatment, and our study was on step-up therapy for patients who did not have control of their asthma. Also, BADGER was an efficacy trial and we were not powered to look at safety outcomes. The duration of our trial and the size of our sample precluded statements regarding long-term risks." In the journal article, the authors write that "clinicians who prescribe LABAs (never to be used as monotherapy) in combination with [ICS] should continue to evaluate risk-benefit ratios." "This is an exciting study and I have to applaud the authors, as the consortium is really trying to help us grapple with important

Disclosure: This study was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; and the Clinical Translational Science Award program of the National centre for Research Resources. Dr. Lemanske reports numerous financial relationships, which are fully listed in the Journal article. Dr. Oppenheimer reports being a consultant and doing previous research for Merck/Schering, GlaxoSmithKline, and AstraZeneca. References: 1. American Academy of Allergy, Asthma, and Immunology (AAAAI) 2010 Annual Meeting. Presented March 2, 2010. 2. N Engl J Med. Published online March 2, 2010.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Respiratory Study

Allergic rhinitis and quality of life

esearchers investigated the evidence of the relationship between allergic rhinitis and impairment of quality of life. The reviewers used a number of data sources including original articles, reviews and consensus statements entered into the Medline and LILACS databases between 1997 and 2008. The following search terms were used: 'allergic rhinitis'; 'quality of life'; and 'sleep disorders'. The researchers found that Quality of life is often impaired in patients with allergic rhinitis, due to the classic symptoms of the disease (sneezing, pruritus, rhinorrhea and nasal obstruction). In addition, the pathophysiology of allergic rhinitis often disrupts sleep, leading to fatigue, irritability, memory deficits, daytime sleepiness and depression. The researchers noted that the total burden of this disease goes beyond impairment of physical and social functioning. It has also a financial impact, which becomes greater when we consider the evidence that allergic rhinitis is a possible causal factor of co-morbidities, such as

‘

asthma and sinusitis. Nasal obstruction, the most prominent symptom, is associated with sleep disorders, which can have a profound effect on mental health, learning, behaviour and attention. Finally, the authors conclude that allergic rhinitis-a chronic condition that affects adults, adolescents and children-is often underdiagnosed or inadequately treated. The

often affected by sleep disorders. Allergic rhinitis is common in the general population and impairs sleep and social life. This French study set out to assess the impact of duration and severity of allergic rhinitis on the quality of sleep and consequently on everyday living. From a nationwide controlled cross sectional epidemiological study, 591 patients with allergic rhinitis (1 year) were selected. Those with nasal polyps and/or major nasal septum deviation were excluded. Sleepiness was assessed by self administered questionnaires: sleep disorders questionnaire and Epworth sleepiness scale score. Sleep impairment was significantly worse (p ,0.001) with increased severity of allergic rhinitis. Patients with allergic rhinitis reported significantly more use of sedative drugs (p=0.003) and alcohol (p ,0.001). Snoring and sleep apnoea were also reported significantly more often in patients with allergic rhinitis (p ,0.001). Poor quality of sleep induced by allergic rhinitis had an adverse impact on everyday living. A review of the study in the same journal by Anilkumar Pillai, Registrar in Medicine, Ninewells Hospital, Dundee; mentions that there may here may have been an unavoidable element of bias in the study as patients with allergic rhinitis would expectedly have better recall about their sleep quality than the control group interviewed in the general population. The authors conclude that early detection and treatment of sleep disorders in patients with allergic rhinitis would have a positive impact on their social and general well being. Further studies focusing on the mechanisms that link allergic rhinitis with altered sleep are needed.

Nasal obstruction, the most prominent symptom, is associated with sleep disorders,

which can have a profound effect on mental health,

deleterious impact that allergic rhinitis-related sleep disorders have on patient capacity to perform activities of daily living is an important component of the morbidity of the disease. With an accurate diagnosis, there are various available treatments that can reduce the burden of allergic rhinitis. Another French study concluded that patients with severe allergic rhinitis are more

Snoring and sleep apnoea were also reported significantly more often in patients with allergic rhinitis

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learning, behaviour and attention.

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References: 1. J Bras Pneumol. 2010 Feb;36(1):124-33. For further information contact dirceus@ajato.com.br 2. Allergic rhinitis and its consequences on quality of sleep: an unexplored area. Le ´ger D, AnnesiMaesano I, Carat F, et al. Arch Intern Med 2006;166:1744–8.

British Thoracic Society Annual Winter Meeting - by Peter Mas-Mollinedo Report from BTS, London

Disease-specific self-management programme trial for patients with COPD Dr. Stephanie JC Taylor, Centre for Health Sciences, Barts and the London School of Medicine and Dentistry, London

hilst self-management of chronic obstructive pulmonary disease (COPD) may not be suitable - or indeed available - for all patients, a group of 116 patients who took part in the Better Living with Long-Term Airways Disease (BELLA) study in Dagenham found that self-management helped to improve their quality of life. The recently completed BELLA study was designed and carried out against the background that the NHS is giving priority to developing sustainable self-care interventions for chronic illness. The Expert Patient Programme (EPP) is a generic chronic disease self-management course which is planned to be rolled out to 100,000 people per year by 2012. However, randomised clinical trials of self-management interventions for COPD have so far shown inconclusive results - for example, a Cochrane review published in 2007 suggested that self-management of COPD could reduce the number of hospital admissions, but the available data was insufficient to draw firm conclusions or issue evidence-based guidelines.1 Around 3 million people suffer from COPD in the UK; this condition has hitherto proven very difficult to influence and the impact of an effective self-management strategy may potentially be dramatic. A research team led by Dr. Stephanie Taylor designed the BELLA programme as a COPD-specific version of the EPP, with special emphasis on addressing patients’ specific information needs and incorporating professional disease management advice to promote effective selfmanagement in COPD. The results of a randomised controlled pilot study were presented by Dr. Taylor in one of the first sessions of the BTS Winter Meeting 2009. Patients were recruited from primary care and allocated (2:1) to either the BELLA programme or usual care. The BELLA programme involved

weekly group sessions of 2.5 hours, during a period of seven weeks. The St. George Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Scale (HADS), EQ-5D, exercise levels and self-efficacy (confidence) to manage COPD were collected at baseline, two and six months, together with information on costs and healthcare resource use. A total of 116 male (46%) and female patients with a mean age of 69.5 years were included in the study (78 intervention; 38 control). The mean forced expiratory volume in 1s (FEV1) at baseline was 54% of predicted; in addition, 78% of the patients had had unscheduled COPD care in the previous 12 months. The overall course uptake was low only 40% of the randomised patients attended five or more sessions. After six months on the BELLA programme, patients had increased their overall exercise levels by a modest amount, and their healthrelated quality of life as recorded by the EQ-5D tool had improved (Table 1). The economic

analyses indicated that the intervention would have a 70% probability of being cost effective, based on an assumed willingness-to-pay threshold of £10,000 per quality-adjusted life year (QALY) gained. The low uptake levels indicate that the BELLA programme in its current form may not be to everybody’s taste but the researchers were encouraged by the positive outcomes and work is currently underway to improve recruitment and enhance the overall appeal and accessibility of the courses. In the longer term, the expected programme is expected to reduce unscheduled health care use, improve treatment concordance, increase patients’ quality of life, and reduce the overall costs to society associated with COPD. Reference: 1. Effing T, Monninkhof EM, van der Valk PD, et al. Self-management education for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007; (4): CD002990.

Table 1. Outcomes of the BELLA programme at baseline and 6 months. Control (n=30) Baseline SGRQ Symptoms Activities Impacts Total score

6 months

Intervention (n=61) Baseline

6 months

*Estimated difference (95% CI)

Direction of effect favours

58.0 57.3 34.4 45.3

50.4 58.7 31.8 43.1

54.9 55.5 36.6 45.4

52.5 53.0 33.9 42.8

4.7 (-3.0 to 12.4) -4.8 (-11.3 to 1.8) -0.3 (-5.1 to 5.7) -0.4 (-5.1 to 4.4)

Control Intervention Intervention Intervention

Strengthening exercise (min/week)

22.0

9.0

22.6

21.6

12.4 (-3.8 to 28.6)

Intervention

Aerobic excersie (min/week)

56.0

43.5

65.7

59.1

10.1 (-16.3 to 35.5)

Intervention

Self-effcacy to communicate with doctors

8.0

7.7

8.5

8.2

0.2 (-0.6 to 1.1)

Intervention

Self-effcacy to manage disease

7.4

7.8

7.6

7.4

-0.5 (-1.0 to 0.1)

Control

HADS Anxiety Depression

6.7 4.8

6.7 5.1

6.1 5.4

5.7 5.7

-0.5 (-1.8 to 0.9) 0.2 (-0.8 to 1.3)

Intervention Control

EQ-5D

0.76

0.57

0.73

0.68

0.12 (-0.02 to 0.26)

Intervention

*Using ANCOVA, regression coeffcient of intervention versus control.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

American College of Cardiology - by Xxxxxx xxxxxx Reports from the ACC, Orlando

Blood pressure that is too low may be harmful Lower is not necessarily better for blood pressure control in patients with diabetes and coronary artery disease, a secondary analysis of a randomised trial showed.

here was no difference in a composite endpoint of death, myocardial infarction, or stroke between patients with an average systolic pressure 130-140mm Hg and those with a lower average pressure, according to Rhonda Cooper-DeHoff, PharmD, of the University of Florida in Gainesville. As expected, patients who had uncontrolled systolic blood pressure (140mm Hg and higher) had significantly increased cardiovascular risk, she reported at the ACC annual scientific meeting. Patients who were most tightly controlled, however, had an increased risk of all-cause mortality compared with those in the middle range, during both the trial and an extended follow-up of about five years. "We probably can rethink lower goals in this particular population and put our efforts toward lifestyle modifications and other things where we can achieve benefit," Cooper-DeHoff said. Past ACC president W. Douglas Weaver, MD, of the Henry Ford Health System in Detroit, who moderated a press briefing at which the results were discussed, found a mixed message in the results. "So I guess the take away is that getting good blood pressure control is good. Getting perfect blood pressure control may not be so good," he declared. Although guidelines recommend keeping systolic pressure below 130mm Hg in diabetic patients (with no lower boundary), evidence to support that guidance is lacking, Cooper-DeHoff said. To explore the issue, she and colleagues performed a prespecified secondary analysis of diabetic patients in the INVEST trial, which compared two blood pressure-lowering strategies in 22,576 patients with coronary artery disease and hypertension. One approach led with the calcium channel blocker verapamil, followed by the ACE inhibitor trandolapril and hydrochlorothiazide as needed. The other led with the beta-blocker atenolol, followed by hydrochlorothiazide and trandolapril as needed. There were no differences between the strategies in blood

pressure control or on the primary endpoint of cardiovascular events. In this secondary analysis, 6,400 patients with diabetes were grouped in thirds, according to the mean ontreatment systolic blood pressure control achieved during the trial: • Uncontrolled (140mm Hg or higher) • Usual control (at least 130mm Hg but less than 140mm Hg)

‘

We probably can rethink

that it was a secondary analysis of a randomised trial, and thus, represented observational data. In addition, she said, the blood pressure levels during the extended follow-up were unknown. Finally, she said, the findings might not be generalisable outside the specific population of diabetics with coronary artery disease. Michael Crawford, MD, of the University of California San Francisco, who served as a moderator of the session at which the results were presented, also noted that patients in the uncontrolled group required a greater number of medications than the other two groups and got worse control as a result. "This suggests that this is a unique group of patients with very difficult-tocontrol blood pressure, and so these data may not be applicable to someone who comes in on no drugs or on one drug and has a blood pressure of 145," he said. "So this may not be broadly applicable."

lower goals in this particular population

and put our efforts toward lifestyle

modifications and other things where

’

we can achieve benefit

• Tight control (less than 130mm Hg). As expected, the uncontrolled group had a significantly higher rate of death, MI, or stroke (19.8%, P<0.0001). But the tight and usual groups had a similar rate on the primary outcome (12.7% and 12.6%, respectively), and on most of the secondary outcomes. However, during the trial, the tight control group had a slightly higher rate of all-cause mortality than the usual control group (11% versus 10.2%, P=0.035). The elevated risk persisted in an extended follow-up lasting about five years in the U.S. cohort of 5,077 patients. After controlling for baseline characteristics, there was a 15% higher risk of all-cause death in the tightly controlled group (HR 1.15, 95% CI 1.01 to 1.32, P=0.036). To further evaluate mortality, the researchers broke the tightly controlled group into two groups. In this group of patients with systolic blood pressure below 130mm Hg, mortality risk was increased only when pressure dropped below 115mm Hg. Cooper-DeHoff acknowledged that the study was limited in

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Disclosure: The trial and analysis were funded by Abbott Laboratories. Cooper-DeHoff reported receiving a research grant from the National Heart, Lung, and Blood Institute. Her co-authors reported relationships with AstraZeneca, AtCor Medical, Daiichi Sankyo, Eli Lilly, Pfizer, sanofi-aventis, Schering-Plough, Juvenile Diabetes Research Foundation, GlaxoSmithKline, Forest Laboratories, CVRx, Merck, Novartis, BoehringerIngelheim, Takeda, Abbott Laboratories, Walgreen's, Bristol Myers-Squibb/Sanofi, Gilead, the National Heart, Lung, and Blood Institute, Baxter, Bioheart Inc., Novartis/Cleveland Clinic, NicOx, Angioblast, NIH, Medtelligence, and SLACK Inc. Weaver reported receiving consulting fees from Phrixis Pharmaceuticals, receiving research grants from Johnson & Johnson, Schering-Plough, and GlaxoSmithKline, and serving on data safety boards for trials sponsored by Boston Scientific, The Medicines Co., Johnson & Johnson, Bayer, Boehringer Ingelheim, and Direct Flow Medical. Crawford reported no conflicts of interest. Reference: 1. Cooper-DeHoff R, et al. Rethinking lower BP goals for diabetics with documented coronary artery disease, findings fom the International Verapamil SR, Trandolapril Study (INVEST). ACC 2010; Abstract.

Prescribing Information CRESTOR® Consult Summary of Product Characteristics (SmPC) before prescribing. Use: In patients unresponsive to diet and other non-pharmacological measures, CRESTOR is indicated for primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), homozygous familial hypercholesterolaemia, or mixed dyslipidaemia. Presentation: CRESTOR is supplied as film-coated tablets containing 5mg, 10mg, 20mg, or 40mg of rosuvastatin. Dosage and administration: The recommended starting dose for all patients (including those being switched from other statins) is CRESTOR 5 or 10mg once daily. The choice of start dose should take into account the patient’s cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions. A dose adjustment to the next dose level can be made after 4 weeks, if necessary. When titrating to the maximum dose of 40mg, specialist supervision is recommended and should only be considered in patients with severe hypercholesterolaemia at high cardiovascular risk. Doses may be given at any time of the day with or without food. Elderly: A start dose of 5mg is recommended in patients >70 years. Asian patients: 5mg recommended start dose. Renal impairment: 5mg recommended start dose in patients with moderate renal impairment (creatinine clearance <60 ml/min). Patients with pre-disposing factors to myopathy: 5mg recommended start dose (refer to SmPC). Children: Safety and efficacy have not been established in children. Contraindications: Hypersensitivity to any of the ingredients; active liver disease or unexplained persistent elevations in serum transaminases; severe renal impairment; myopathy; concomitant ciclosporin; pregnancy and breast-feeding; women of child-bearing potential not using contraception. In addition, CRESTOR 40mg is contraindicated with concomitant fibrates, in patients with predisposing factors for developing myopathy/rhabdomyolysis and patients of Asian origin (refer to SmPC). Precautions: Renal effects: Proteinuria seen in patients treated with higher doses of CRESTOR, in particular 40 mg, where it was usually transient or intermittent. A causal relationship has not been identified between proteinuria and acute or progressive renal disease. An assessment of renal function should be considered

during routine follow-up of patients treated with CRESTOR 40 mg. Muscle effects: Patients with signs and symptoms of myopathy should have their creatine kinase (CK) levels monitored. CRESTOR should be discontinued if CK levels are markedly elevated or, if muscle symptoms are severe and cause daily discomfort. Risk of myositis and myopathy may increase when administered with certain other drugs, combination of CRESTOR with gemfibrozil is not recommended and other fibrates should be used with caution with CRESTOR 5, 10 and 20mg. As with other HMGCoA reductase inhibitors CRESTOR should be prescribed with caution in patients with pre-disposing factors for myopathy and rhabdomyolysis (refer to SmPC). CRESTOR should not be used in patients with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis. Rarely, rhabdomyolysis, occasionally associated with impairment of renal function, has been reported with all doses and in particular with doses >20mg. Liver effects: CRESTOR should be used with caution in patients with a history of liver disease and/or alcoholism. Liver function tests should be carried out, prior to, and 3 months following the initiation of treatment. CRESTOR should be discontinued or the dose reduced if the level of serum transaminases is greater than 3-times the upper limit of normal. Race: Increased systemic exposure has been seen in Asian subjects. CRESTOR 40mg is contraindicated and caution should be used when making other dose decisions in such patients. Pregnancy and lactation: CRESTOR is contraindicated in pregnancy and lactation. Drug interactions: CRESTOR is neither an inhibitor nor inducer of cytochrome P450 isoenzymes. CRESTOR may potentiate the anticoagulant effect of Vitamin K antagonists, monitor International Normalised Ratio (INR) upon initiation, dose adjustment and discontinuation of CRESTOR therapy. Caution should be exercised with concomitant use of CRESTOR and ezetimibe. Decrease in CRESTOR levels seen when co-administered with erythromycin or antacids containing aluminium and magnesium hydroxide. Increase in oral contraceptive level seen when co-administered with CRESTOR. Concomitant use of CRESTOR with protease inhibitors is not recommended. Patients with the rare hereditary problems of galactose intolerance, the Lapp

lactase deficiency or glucose-galactose malabsorption should not take this medicine. Undesirable events: Side effects most frequently reported in controlled clinical studies and post marketing experience: headache, dizziness, constipation, nausea, abdominal pain, myalgia, asthenia. Uncommon: pruritus, rash and urticaria. Rarely: myopathy (including myositis), rhabdomyolysis with and without acute renal failure, hypersensitivity reactions including angioedema, pancreatitis. Very rarely: arthralgia, jaundice, hepatitis, polyneuropathy, haematuria, memory loss. Unknown frequency: diarrhoea, Stevens-Johnson syndrome. Other usually transient side effects: elevations in transaminases and CK levels, proteinuria (refer to SmPC). Legal Category: POM. Marketing authorisation numbers: CRESTOR 5mg PL 17901/0243; CRESTOR 10mg PL 17901/0201; CRESTOR 20mg PL 17901/0202; CRESTOR 40mg PL 17901/0203. Basic NHS price: CRESTOR 5mg (28 tablets), £18.03; CRESTOR 10mg (28 tablets), £18.03; CRESTOR 20mg (28 tablets), £26.02; CRESTOR 40mg (28 tablets) £29.69. Further information is available from the Marketing Authorisation Holder: AstraZeneca UK Ltd, 600 Capability Green, Luton, LU1 3LU, UK. ‘CRESTOR’ is a trademark of the AstraZeneca group of companies. Licensed from Shionogi & Co Ltd, Osaka, Japan. AstraZeneca Medical Information Freephone 0800 783 0033. 12/2008.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to AstraZeneca on 0800 783 0033.

Date of preparation: June 2009 CZ001584-CRES

Finding cholesterol targets harder to hit?

C A R D I O VA S C U L A R

American College of Cardiology - by Xxxxxx xxxxx Reports from the ACC, Orlando

Rosuvastatin and ezetimibe combination success

ore than 95% of patients taking a high dose rosuvastatin plus ezetimibe combination reached low-density lipoprotein (LDL) goals of less than 100mg/dl, a significant improvement over a high-dose combination of simvastatin/ezetimibe. In addition, the high dose rosuvastatin combination was statistically significantly more successful in getting patients to achieve LDL < 70 mg/dl, according to Christie Ballantyne, MD, of the Baylor College of Medicine in Houston.

‘

The randomised, open-label, 12-week study was aimed at determining how great a reduction each arm could achieve. The reduction from baseline with the low dose rosuvastatin combination was 59.7%, significantly superior to the low dose simvastatin combination, 55.2% (P<0.05). Treatment with the high-dose rosuvastatin combo reduced LDL cholesterol 63.5% compared with a reduction of 57.4% with the high-dose simvastatin combination (P<0.001). In an analysis of LDL-lowering goals, the

Many researchers believe that cholesterol-lowering treatment regimens cannot produce reductions

’

below 60% of baseline

"Our results are kind of what you would have expected," Ballantyne said at his poster presentation at the 2010 American College of Cardiology annual scientific meeting. Many researchers believe that cholesterol-lowering treatment regimens cannot produce reductions below 60% of baseline, but with high-dose rosuvastatin 20mg/ezetimibe 10mg, the investigators observed a mean 63.5% decrease in LDL among the patients assigned to that treatment. In the GRAVITY trial (Gauging the lipid effects of RosuvAstatin plus ezetimibe Versus sImvastatin plus ezetimibe TherapY), Ballantyne and colleagues assigned the following patients and drugs regimens:

researchers observed that 93.3% of the low dose rosuvastatin and 95.6% of the high dose rosuvastatin patients reached the LDL goal of less than 100mg/dl, compared with 87.4% of those on the low dose simvastatin (P<0.05) and 88.6% of those patients on high dose simvastatin (P<0.05). They also found that

67.1% of the low-dose rosuvastatin patients achieved LDL-lowering to below 70mg/dl, compared with 55.3% of the low dose simvastatin patients (P=NS). And 77% of high dose rosuvastatin combination patients reached the goal, compared with 67.7% of the high-dose simvastatin patients (P<0.001). "Adverse side effects were very low in all arms of the study," Ballantyne said. "It is reassuring that people were able to reach these LDL goals," said Sidney C. Smith, Jr., MD, professor of medicine at the University of North Carolina, who was not involved in the study. However, noting controversy that has swirled about the use of ezetimibe, Smith said, "We need to perform outcome studies with these drugs." Disclosure: The study was sponsored by AstraZeneca. Ballantyne disclosed financial relationships with Abbott BristolMyers Squibb, GlaxoSmithKline, Kowa, Merck/Schering Plough, Metabasis, Novartis, Pfizer, Sanofi-Synthelabo, Schering-Plough, Takeda, AstraZeneca, Merck. Reference: Ballantyne C et al. randomised comparison of rosuvastatin plus ezetimibe versus simvastatin plus ezetimibe: Results of the GRAVITY study. ACC 2010; Abstract 1019-98

Full reports from the American College of Cardiology annual scientific meeting can be found on

• 214 patients rosuvastatin 10mg plus ezetimibe 10mg • 214 patients to rosuvastatin 20mg/ezetimibe 10mg • 202 patients to simvastatin 40/ezetimibe 10mg • 203 patients to simvastatin 80/ezetimibe 10mg

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

a request-only electronic journal. Please email: subscriptions@icr-uk.com and mark your email ‘Cardiology.MED’

NAVIGATOR confirms diet and exercise still best

wo strategies aimed at preventing cardiovascular events in high-risk patients, use of an angiotensin receptor blocker or a short-acting insulin secretagogue for five years, failed to reduce myocardial infarction or stroke. Patients randomised to valsartan (Diovan) did achieve a 14% relative reduction in the incidence of diabetes (P<0.001), but even that benefit was less than the 25% to 30% decline in incidence reported in previous trials of ACE inhibitors, said Robert M. Califf, MD, of Duke University Medical Centre in Durham, N.C., lead investigator for the study. In order to achieve a 14% reduction in new onset diabetes, it would require treating 1,000 patients with valsartan for five years. Califf and Rury R. Holman, MB, ChB, of Oxford, reported results of the NAVIGATOR study during a latebreaking clinical trials session at the American College of Cardiology meeting. The results were also published online by the New England Journal of Medicine. The incidence of MI, stroke, or hospitalisation for heart failure was 14.5% in the valsartan arm and 14.8% in the placebo group. For patients randomised to the insulin secretagogue nateglinide (Starlix), the cardiovascular endpoint was 7.9% versus 8.3% in the placebo arm. NAVIGATOR randomised 9,306 patients with impaired glucose tolerance and either established heart disease or a combination of risk factors that put them at high risk for cardiovascular events to either valsartan, nateglinide, or matched placebo on top of a lifestyle intervention. The intervention was designed to help patients lose at least 5% of body weight, reduce fat intake, and increase exercise. Valsartan was dosed at 80mg daily for two weeks followed by an increase to 160mg daily. Nateglinide was dosed at 30mg three times a day before meals for two weeks then increased to 60mg, three times a day. The average age of patients was 63 and half were women. About one-quarter of the patients had established cardiac disease as opposed to risk factors for same. There were three coprimary endpoints, new onset diabetes, a core cardiovascular endpoint that combined MI, stroke, or hospitalisation for heart failure, and

five-year progression of cardiovascular disease as measured by components of the core cardiovascular endpoint and hospitalisation for angina or revascularisation. The most unexpected finding of the study was the failure of nateglinide to prevent progression to diabetes in patients with impaired glucose tolerance. The NAVIGATOR investigators wrote that they thought nateglinide "might reduce the risk of progression to diabetes by restoring a more physiologic insulin response to meals than that which occurs with sulfonylureas." But they found, "that nateglinide offers no protection from the progression of impaired glucose tolerance to diabetes or from the progression of cardiovascular disease, and possibly raises glucose levels after a glucose challenge." One bright note, nateglinide did not increase cardiovascular risk, which has been a concern with some oral glucose-lowering agents. It did, however, increase the risk of hypoglycaemia. Holman said the study did confirm the value of weight loss, diet, and exercise. Lifestyle intervention, he said, appears to be the best option for primary and secondary prevention. And the authors wrote that even the slight benefit seen with valsartan may have clinical implications "since the use of both thiazide diuretics and beta-blockers has been associated with an increased risk of diabetes." But in an editorial that accompanied the journal publication Harvard's David M. Nathan, MD, didn't buy that argument because while valsartan did not worsen glycemia it "was relatively weak in preventing diabetes, and it did not lower the rates of cardiovascular disease." Nathan concluded that, for now, "we should steer away from these two drugs and use effective lifestyle interventions and, in selected persons, metformin to combat the

epidemic." One limitation noted in the study was that the valsartan arm had a high rate of patients discontinuing the drug and those in the matched placebo group had a high rate of taking ACE inhibitors or other ARBs. Disclosures: The trial was sponsored by Novartis. Holman reported receiving grant support, consulting fees or lecture fees from Asahi Kasei Pharma, Bayer Healthcare, Bayer Schering Pharma, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Merck Serono, Novartis, Novo Nordisk, Pfizer, sanofi-aventis, Amylin, Eli Lilly, Astella, King Pharmaceuticals, and Takeda. Califf reported receiving research grant support or consulting fees from Novartis Pharmaceuticals, Johnson & Johnson/Scios, Lilly, Merck, Schering Plough, Annenberg, Aterovax, Bayer/Ortho McNeil, BMS, Boehringer Ingelheim, GlaxoSmithKline, WebMd/theheart.org, Kowa Research Institute, McKinsey & Company, Medtronic, Novartis, and sanofiaventis, and an equity position with NITROX, LLC. Califf said "all personal income from industry relations is donated to non-profit entities." Nathan declared he had no financial conflicts. References: NAVIGATOR study group. Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events. N Engl J Med 2010; 10.1056/NEJMoa1001122. NAVIGATOR Study Group. Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events. N Engl J Med 2010; DOI 10.1056/NEJMoa1001121. Nathan, DM. Navigating the Choices for Diabetes Prevention. N Engl J Med 2010; DOI: 10.1056/NEJMe1002322.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

American College of Cardiology - by Marybeth Burke Reports from the ACC, Orlando

Blood pressure variation predicts stroke better than average values

University Hospital, cautioned that it would be premature to change practice on the basis of these reports. "More studies need to be done to better characterise the effects of different classes of antihypertensive drugs on long-term blood-pressure variability. Moreover, further study of the relation of blood-pressure variability to the risk of different types of stroke (e.g., cardioembolic, large-vessel disease, and small-vessel disease, etc.) is important," they wrote. Carlberg and Lindholm also noted that "results from clinical trials with standardised recordings and treatment care are difficult to

Carlberg's and Lindholm's commentary and two of the papers by Rothwell and colleagues were published The Lancet. Their third study, focusing on calcium channel antagonists and beta blockers in the previous stroke studies, and Gorelick's commentary appeared online in Moreover, some antihypertensive drugs are Lancet Neurology. better than others at controlling blood pressure As Carlberg and Lindholm pointed out, variability, according to three new reports in hypertension is a well-known risk factor for The Lancet, all by Peter M. Rothwell, MD, PhD, cardiovascular disease but the exact of John Radcliffe Hospital in Oxford, England, mechanisms are not understood. Several and colleagues. previous studies, in addition to those highlighted by Rothwell and colleagues, have The researchers reported that: found that antihypertensive drugs have • Patients participating in several sometimes been more effective in previous cohort studies whose visitreducing rates of cardiovascular events to-visit variation in systolic blood than could be accounted for solely by pressure was in the highest decile had their effects on average blood pressure, hazard ratios ranging from 3.25 to and variability in blood pressure has 6.22 (P<0.0001) for stroke compared been suggested as an explanation. But with those in the lowest decile. these new findings by Rothwell and • A meta-analysis of 389 randomised colleagues appear to make the case trials involving different classes of more strongly than before, because antihypertensive medications found they found confirmation in a variety of that calcium channel blockers were Dr. Bo Carlberg and Dr. Lars Hjalmar Lindholm different trials analysed in different most likely to reduce blood pressure ways. In one of The Lancet papers, they variability, whereas ACE inhibitors, translate into everyday practice in which re-examined data from the so-called UK-TIA beta blockers, and angiotensin receptor patients often receive several different drugs trial in which 2,435 patients with a recent antagonists tended to worsen it. that can change over a short time." They transient ischemic attack or ischemic stroke • This effect appeared to explain why results suggested that clinicians wait for the findings to were randomised to aspirin or placebo from earlier trials showed that calcium be replicated in additional data sets. Already conducted in the 1980s. Blood pressure was channel antagonists were better than beta under way is an analysis of blood pressure measured frequently in this trial - more than blockers at reducing the risks of stroke when variability and major cardiovascular events in half the participants had at least seven their effects on average blood pressure were more than 200,000 participants in the Blood measurements, allowing Rothwell and the same. Pressure Lower Treatment Trialists' colleagues to test their hypotheses about Collaboration, Carlberg and Lindholm variable versus average pressure. They found "Stable hypertension has a better prognosis indicated. On the other hand, Philip Gorelick, that a high mean systolic pressure was a much than does episodic hypertension," Rothwell MD, MPH, of the University of Illinois in weaker predictor of subsequent stroke (hazard and colleagues concluded in one of the reports, Chicago, indicated that clinicians may ratio 2.44 for the top versus bottom decile after in contrast to the traditional view that reasonably incorporate at least some of the adjusting for other standard risk factors, 95% intermittent high blood pressure may be safely Lancet studies' findings into their practices CI 1.56 to 3.82) than a large standard deviation ignored. In an accompanying commentary, two now. "Clinicians should give careful in systolic pressure over repeated Swedish researchers said the findings "give consideration to use of drugs associated with measurements, (HR 6.22, 95% CI 4.16 to some plausible explanation to previously low variability in blood pressure," he wrote in a 9.29). The researchers then confirmed these unanswered questions." But, Bo Carlberg, MD, separate commentary in Lancet Neurology. findings with data from three additional PhD, and Lars Hjalmar Lindholm, MD, of Umeå lood pressure variability over time, not merely its average level, is a powerful risk factor for stroke, myocardial infarction, and other cardiovascular events.

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Hypertension is a well-known risk factor for cardiovascular disease but the exact mechanisms are not understood.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

’

published cohorts: ASCOT-BPLA (subgroup of 2,011 patients with previous TIA or stroke), European Stroke Prevention Study-1 (ESPS-1) with 2,500 patients, and a Dutch TIA Trial (3,150 patients), which all found highly significant risks for stroke in patients with highly variable blood pressure. After adjusting for mean BP, the hazard ratios for stroke in the top versus bottom deciles of variability in these four cohorts ranged from 1.78 (95% CI 1.21 to 2.62) in ESPS-1 to 4.84 (95% CI 3.03 to 7.74) in the UK-TIA study. In the accompanying metaanalysis of randomised trials, Rothwell and colleagues pooled data from 389 studies that reported mean systolic pressure, with standard deviations, before and after treatment with different antihypertensive drugs. The drug classes covered were: • Calcium channel antagonists (134 studies) • Non-dihydropyridine calcium channel antagonists (33 studies) • Non-loop diuretics (58 studies) • ACE inhibitors (160 studies) • Angiotensin receptor antagonists (61 studies) • Beta blockers (96 studies) • Alpha-1 blockers (13 studies) • Placebo (119 studies) Data for each drug class was pooled from these studies, with the treatment-related change in inter-individual variance (the square of the standard deviation) in systolic pressure calculated. The primary outcome measure was the variance ratio, the variance for each drug class divided by the variance for all other classes combined. The largest treatment-related reductions in variance were seen with calcium channel antagonists, with a variance ratio of 0.81 (95% CI 0.76 to 0.86), followed by nonloop diuretics (VR 0.87, 95% CI 0.79 to 0.96). In contrast, the variance increased with some other drugs: • ACE inhibitors: VR 1.08, 95% CI 1.02 to 1.15 • Angiotensin receptor antagonists: VR 1.16, 95% CI 1.07 to 1.25 • Beta blockers: VR 1.17, 95% CI 1.07 to 1.28 Rothwell and colleagues also found that the effects of treatment on the variance ratio were significantly associated with rates of stroke. A variance ratio of 0.8 or less was associated with an odds ratio of 0.79 (95% CI 0.71 to 0.87) for stroke in the pooled data, the researchers indicated. Treatment effects on mean systolic pressure reduced stroke risk to a similar degree. In the Lancet Neurology report, Rothwell and colleagues took a closer look at calcium channel

antagonists and beta blockers and their effects on stroke risk in the ASCOT-BPLA cohort along with participants in yet another previous study, the Medical Research Council (MRC) trial. ASCOT-BPLA was a randomised comparison of atenolol with amlodipine, whereas the MRC trial was a three-way study of atenolol, hydrochlorothiazide, and placebo. A total of about 19,000 patients took part in ASCOTBPLA; the MRC study had some 4,400 participants. Rothwell and colleagues found that, in ASCOTBPLA, the standard deviation in group systolic pressure readings "was lower in the amlodipine group than in the atenolol group at all followup visits ... mainly because of lower within-individual, visit-to-visit variability," they wrote. Patients taking amlodipine had a 22% reduction in stroke rates compared with those on atenolol (95% CI 10% to 33%). Adjusting for mean systolic pressure decreased the effect on stroke risk by about one-third. But it was completely abolished when Rothwell and colleagues also adjusted for intra-individual variation in systolic pressure. The MRC trial participants showed greater variability in systolic pressure with atenolol versus either the diuretic or placebo, both in group standard deviation and all measures of intra-individual variation, the researchers indicated. "To prevent stroke most effectively, blood-pressurelowering drugs should reduce mean blood pressure without increasing variability; ideally they should reduce both," the researchers concluded. "Rothwell and colleagues are to be congratulated for bringing forth compelling findings that eventually might set the foundation for a major change in our practice of blood pressure treatment for the prevention of stroke or other cardiovascular diseases," Gorelick enthused. Carlberg and Lindholm, taking a more restrained view, said the findings were "challenging and will raise many questions." In

particular, they suggested that future research investigate the relationship between visit-tovisit blood pressure variation and arterial stiffness, as it is unknown whether these phenomena share the same causes. Another important question is whether lifestyle factors such as exercise, stress, smoking, salt intake, and body weight affect variability in blood pressure, Carlberg and Lindholm wrote.

Disclosure: Support for the data analysis reported here came from a variety of government and nonprofit sources including the U.K. Medical Research Council and National Institute for Health Research. Many of the trials on which the study was based were funded by pharmaceutical companies; e.g., Pfizer and Servier provided funding for the ASCOT-BPLA trial. Study authors reported relationships with Pfizer, Servier, Merck, Novartis, Boehringer Ingelheim, Daiichi Sankyo, and Mintage Scientific. Carlberg and Lindholm reported no relationships with commercial entities. Gorelick reported relationships with Daiichi Sankyo, Novartis, Boehringer Ingelheim, and Pfizer. References: Rothwell P, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010; 375: 895-905. Webb A, et al. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375: 906-15. Carlberg B, et al Stroke and blood pressure variation: New permutations on an old theme. Lancet 2010; 375:867-69. Rothwell P, et al. Effects of beta blockers and calciumchannel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010; DOI: 10.1016/S1474- 4422(10)70066-1. Gorelick P. Reducing blood pressure variability to prevent stroke? Lancet Neurol 2010; DOI: 10:1016/S14744422(10)70067-3.

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p26 allmarket doc letter

24/3/10

16:18

Page 1

INVITATION TO JOIN OUR DOCTOR RESEARCH PANEL Dear Doctor,

Allmarket Europe Ltd is a company that provides market research services to the pharmaceutical industry. One of the methods we use to collect data is from an on-line panel of doctors whom we have recruited. Due to an expansion of our business we currently have a requirement to recruit more UK doctors, and we would like to invite you to join our panel.

The panel scheme works as follows: If you agree to join the panel we will occasionally email you a link to our website which will give you access to a questionnaire. We will tell you the subject matter of the questionnaire, how long it will take to complete (usually between 5 and 8 minutes), and how much we will pay for the completed questionnaire - typically ÂŁ40 - ÂŁ55. If you have the time and inclination to complete, you just click on the link and complete the questionnaire. Otherwise ignore it. The big advantage of this type of research is that you can complete the questionnaire at a time of your choosing. Completed questionnaires trigger an automatic payment. We would anticipate sending out a questionnaire every eight to twelve weeks. We would like to stress that all replies are in strict confidence and only collated data are disclosed to our Clients.

To qualify for the panel you need to be a GP or secondary care practitioner with access to the Internet, give us your contact details, and allow us to use your email address to send the link to. We would like to stress that your email address will never be disclosed to a third party. If you would like any further details about the panel scheme, or ourselves - please contact us at annie@icr-uk.com.

If you would like to join our panel, please send us an email with your contact details - name, address, telephone number and indicate whether you are a GP or hospital doctor and what your area of interest is. This is all in strict confidence. We will then send you a PIN number, which you enter on the questionnaire - this saves you having to enter your name and address each time you complete a questionnaire.

Thank you for taking the time to read this correspondence, and I hope to welcome you to our panel in the near future. Yours sincerely,

Peter Mas-Mollinedo Managing Director.

Allmarket Europe Ltd.

ICR-UK Limited, PO Box 448, West Byfleet KT14 9AU Phone: 0845 094 1699 Fax: 0845 094 1690

EMEA Highlights - by Gary Finnegan

Emerging Uses of EMEA-Approved Drugs TRANSATLANTIC AGREEMENT ON ORPHAN DRUGS

he European Medicines Agency and the US Food and Drug Administration (FDA) have agreed to accept a single annual report from companies making orphan medicines for sale in Europe and the US. The move will help cut down on red tape for manufacturers and make it easier for authorities on both sides of the Atlantic to share information. Until now, licence holder have had to submit separate reports to each agency, often at different times, but will now be able to file a just once and the authorities will exchange the annual reports electronically through a secure portal. The new facility was launched on World Rare Diseases Day on February 28. Professor Kerstin Westermark, Chair of the EMA Committee for Orphan Medicinal Products said regulators are working towards greater simplification. “This new step in our collaboration provides each of our agencies with information in real time on any challenges arising during the development of products for rare diseases and will help identifying and acting on bottlenecks,” he said.

CONSULTATION ON ‘ROAD MAP TO 2015’

he European Medicines Agency (EMA) has launched a wide consultation on its priorities for the next five years. Doctors, patients and the pharmaceutical industry can have their say on the strategy, dubbed Road Map to 2015, until April 30. A number of workshops will then be held as part of the consultation process before the five-year Road Map is finally adopted by the Agency’s management board in December 2010.

The document proposes three areas for future action: public health, access to medicines, and drug safety. The EMA is pledging to stimulate medicine research in areas of unmet need and for rare diseases and is aiming to improve its medicines review process to make it more consistent.

NEW RECOMMENDATIONS FROM CHMP

he CHMP has given conditional backing to a fifth pandemic vaccine. Humenza, from Sanofi Pasteur, is intended for the prophylaxis of influenza in an officially declared pandemic situation. This recommendation was made using an emergency procedure which fasttracks evaluation of new vaccines developed during a pandemic. The Committee also adopted a positive opinion for: Votrient (pazopanib), from Glaxo Group Ltd, intended for the treatment of patients with advanced renal cell carcinoma. At its February meeting, the CHMP extended the therapeutic indication for Cholestagel (colesevelam) from Genzyme Europe. Cholestagel can now but used in combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia. An extended indication was approved for Tyverb (lapatinib) from Glaxo Group Ltd. The drug can now be used in the treatment of patients with breast cancer whose tumours overexpress HER2 (ErbB2), in combination with an aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic disease, not currently intended for chemotherapy. The patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor. Another new medicine from the same company has been granted “conditional approval”, meaning further evidence on the drug is awaited. Arzerra (ofatumumab) is

intended for the treatment of patients with chronic lymphocytic leukaemia who are refractory to fludarabine and alemtuzumab. The Agency has also concluded a review of Tysabri (natalizumab) from Elan Pharma International Ltd, on the risk of progressive multifocal leukoencephalopathy (PML), a rare brain infection caused by the JC virus. The Committee concluded that the benefits of this medicine continue to outweigh its risks for patients with highly active relapsingremitting multiple sclerosis, but recommended further measures to manage the risk of PML.

FIRST DRUG APPROVED FOR COMPASSIONATE USE

n experimental use of a new medicine has been approved on compassionate grounds for the first time in Europe. The EMA’s Committee for Medicinal Products for Human Use (CHMP) has decided to allow critically-ill patients in Finland to use an intravenous formulation of oseltamivir (Tamiflu IV). The recommendation is not mandatory and each EU country can decide whether or not to adopt the Agency’s decision. The original request from Finland relates to patients with suspected or confirmed pandemic or seasonal flu who cannot take authorised antivirals by mouth or as an inhalation. Oseltamivir is already authorised for oral use but there is limited data available on its intravenous use. Compassionate use programmes are intended to give patients with a life-threatening, long-lasting or seriously disabling disease, who have no available treatment options, access to treatments that are still under development and that have not yet been authorised. A separate application for compassionate use has also been granted to GlaxoSmithKline Research & Development for the use of IV Zanamivir in critically ill patients suffering from pandemic or seasonal influenza.

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Medical news from around the world - by Gary Finnegan

World Health Matters

CHINA INFANT INJURY MORTALITY HIGHER IN RURAL CHINA Significant urban-rural disparities have been uncovered between the death rates from serious injuries among infants in China, with suffocation considerably more likely in rural areas. A new Chinese study, backed by Johns Hopkins Centre for Injury Research and Policy, found that rural males of all ages were 47% more likely to die from injuries than urban males, and the overall rate in rural females was 33% higher than in urban females. For babies less than one year of age, unintentional suffocation was the most important source of the total urban-rural disparity, whereas drowning was the great contributor to disparity among children ages one to four years. At the other end of the age spectrum, suicide accounted for the bulk of the disparity for both men and women. The report, published in the Journal of Rural Health1, is based on data collected by the Chinese Death Cause Registry, which covers about 10% of the total population. The sample, which exceeds 100 million people, has been shown to be a representative sample of

the total population. “While our research did not investigate causes behind the disparities, previous research has shown that rural residents of China have more law violations and high-risk behaviours than urban residents, such as driving after drinking, driving without a license, storing pesticides at home, and using rat poison at home. Studies worldwide have also linked higher injury mortality rates to longer times for response and transport to medical care in rural areas,” said Dr. Guoqing Hu, lead study author and associate professor of epidemiology and health statistics at Central South University in China. “Further research is needed to develop effective interventions for reducing injuries and narrowing the urban-rural gap in injury mortality in China,” said Hu. Prof Susan Baker of Johns Hopkins University said the stark contrast between urban and rural injury mortality figures should help authorities to bridge the divide. “As good policy decisions rely on the availability of good data, the objective of this study was to provide information on urban-rural disparities in injury mortality in China, so as to offer a basis for governmental decisions related to injury interventions. The findings should be used to set priorities for reducing the high rate of fatal injuries in rural China,” she said. Reference: 1. J Rural Health. 2010 Winter;26(1):73-7

GERMANY ‘PSYCHOSURGERY’ RETURNS FOR PSYCHIATRIC DISORDERS Psychosurgery is making a comeback after studies showed promising results for the use of deep brain stimulation (DBS) in the treatment of often intractable conditions. A new review of the evidence spanning a three decades reveals DBS can be effective in

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patients with treatment-resistant obsessivecompulsive disorder, depressive disorders, and Tourette syndrome. Writing in the journal Deutsches Ärzteblatt International 1, Jens Kuhn of the University of Cologne and Theo Gründer at the Max Planck Institute, Cologne, offer a cautious but broadly positive assessment of clinical evidence from the year 1980 to 2009. DBS is already well established in the treatment of some movement disorders, and a series of recent case studies prompted the Cologne group to investigate its use for psychiatric conditions. They found improvement rates of between 35% and 70% in treatment-resistant obsessive-compulsive disorder, depression, and Tourette syndrome. The rate of side effects associated with DBS was usually low and mostly reversible by modulating the stimulation parameters. According to the authors, this favourable side effect profile is not surprising given that DBS is a well-established procedure. In Parkinson's disease and essential tremor, the method has proved to be so effective that it has been licensed as a therapeutic option for many years. However, the authors note that the evidence base is still far from complete, adding that any surgical intervention requires ethical reflection. DBS requires the implantation of two electrodes into the patient’s brain, enables modulation of the functional neuronal circuits by delivering continuous, high-frequency electrical pulses. “Although no global power of effect can currently be determined, the published results of the treatment of refractory psychiatric diseases with DBS can be considered promising. In the majority of cases there has been a distinct improvement in the psychiatric status of these severely ill and previously untreatable patients,” the authors write. The many case reports have been complemented by an increasing number of pilot studies, some of them with randomised, blinded stimulation phases. Further data will be needed if DBS is to become a mainstream option for difficult-totreat psychiatric conditions, according to the report. “To date, the documented adverse effects of DBS in patients with psychiatric diseases are minor, often reversible by adjustment of the treatment parameters or well

tolerated by the patients. Nevertheless, there are no long-term data,” say Kuhn, Gründer and colleagues. Reference: 1. Dtsch Arztebl Int 2010; 107(7): 105–13

UNITED STATES RESEARCHER UNCOVER PERSONALISED BIOMARKERS FOR TUMOUR DNA Researchers in the United States have developed a new technique for tracking cancer by identifying personalised biomarkers from tumour DNA, according to a new study in published in the journal Science Translational Medicine. The authors believe their findings show that next-generation sequencing technology is poised to become an important tool in the new era of personalised management of cancer patients. “There is currently no test for cancer patients that provides personalised biomarkers for clinical management of disease, and we feel that this is an important step in bringing new genome sequencing technologies to personalised patient care,” said Victor Velculescu, associate professor of oncology and Co-Director of the Cancer Biology Program at Johns Hopkins. Keeping cancer cells under control requires the ability to monitor residual and recurrent tumours in order to assess whether or not treatment is working. Based on discovering cancer-related changes in DNA, the personalised Analysis of Rearranged Ends (PARE) approach provides a highly accurate and specific way to monitor tumours, by searching for the “genetic bread-crumb trail” left by lingering cancer cells after surgery or during drug therapy. “We believe that this is one of the first applications of new genome sequencing technologies that could be useful for cancer patients,” said Velculescu. A nearly universal feature of human cancer is the widespread rearrangement of DNA. Yet historically, it has been difficult to accurately map such changes in individual tumours. Now, Velculescu and colleagues have used PARE to identify a handful of rearranged DNA sequences in four colorectal and two breast tumours. Since these rearranged sequences are present only in tumour DNA but not in normal

DNA, the researchers were able to create personalised biomarkers or “red flags” based on these unique sequences. They used the biomarkers to hunt down tiny amounts of tumour DNA meshed within large quantities of normal DNA in blood and other bodily fluid samples - as could easily be done following surgical removal of tumours or other therapies. “PARE uses genetic characteristics unique to the tumour to monitor disease progression. By exploiting rearrangements specific to the patient's tumour, we have developed a personalised approach for detection of residual disease,” said co-author Rebecca Leary, graduate student at the Johns Hopkins Kimmel Cancer Centre. However, PARE is expensive and its $5,000 price tag will be a major barrier to be overcome if the new technique is to come into widespread use. Nonetheless, this approach may profoundly alter how the effectiveness of cancer treatments like radiation, chemotherapy, and surgery are assessed in individual patients. The authors also expect the cost to fall over time. “As PARE becomes affordable, it will be a helpful addition for physicians to tailor patient care and may become a useful supplement to traditional monitoring by imaging or other approaches,” said Leary.

DENMARK DANES DISCOVER SIMPLE WAY TO LIMIT AMI TISSUE DAMAGE Doctors at Aarhus University in Denmark believe they may have identified a simple and safe way to limit tissue damage in patients with acute myocardial infarction (AMI). By repeatedly inflating a blood pressure cuff, paramedics can contain the long-term impact of heart attack. Repeated lack of oxygen for short periods of time in a distant organ can protect another organ - such as the heart - during a subsequent tissue damaging period due to oxygen deficiency. The principle can be applied before predictable oxygen deficiency during heart surgery. However, in most patients heart attacks are unpredictable.

In a randomised single-blinded trial, investigators in Denmark, led by Professor Hans Erik Bøtker supported by colleagues from the UK and Canada, tried to determine whether remote ischemic conditioning during evolving myocardial infarction could have a protective effect and decrease heart tissue damage in patients later undergoing acute balloon dilatation. A total of 333 Danish patients were assigned to receive remote conditioning or no conditioning during ambulance transportation to the hospital for acute balloon dilatation. In the group receiving remote conditioning a blood pressure cuff was placed on the upper arm and inflated to 200mmHg for 5 minutes to stop blood supply to the arm, and then released for another 5 minutes to restore blood flow. The procedure was repeated four times during transportation. On average the amount of heart tissue saved was 30% higher in patients receiving remote conditioning compared to those receiving standard care. This increased to 50% among those with the highest amount of heart tissue threatened by coronary occlusion. Limitation of tissue damage resulted in improved heart function during hospitalisation. The underlying mechanisms are thought to be activation of protective systems in the heart. This induces resistance to tissue damage during lack of oxygen in particular when opening the occluded artery by balloon dilatation. The investigators characterise the treatment as inexpensive and promising, and predict that it will have widespread potential for the treatment of not only heart attack but also other diseases such as stroke. However, larger studies are needed to establish the precise benefits in patients. It also needs to be clarified whether the new treatment can reduce mortality and development of heart failure following a heart attack.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Journal Reviews - by Bruce Sylvester

Reporting from some of the latest articles in

The BIG FOUR www.nejm.org

SIGNIFICANT PROMISE IN TREATMENT OF MULTIPLE SCLEROSIS

esearchers reported in the recent issue of the New England Journal of Medicine that treatment of multiple sclerosis with the oral drug Cladribine significantly reduces relapse and deterioration in the disease, and has a lower side-effect profile that existing therapies. Cladribine could become the first ever treatment in tablet form for MS, and, notably, is taken just 8 to 10 days a year, eliminating injections and intravenous infusions. Cladribine is currently indicated for the treatment of symptomatic hairy cell leukemia (HCL). Multiple sclerosis results from the body's own immune system damaging the central nervous system, resulting in interference in transmission of messages between the brain and other parts of the body. This causes problems with vision, muscle control, hearing and memory. Cladribine suppresses the immune system in such a way that it compromises its ability to attack the central nervous system. The study was led by Professor Gavin Giovanonni at Barts and The London School of Medicine and Dentistry. It enrolled over 1,300 MS patients. They were followed for nearly two years and monitored using MRI scans. Patients received either 2 or 4 short treatment courses of Cladribine tablets per year, or a placebo. Each course consisted of 1 or 2 tablets per day for 4 or 5 days, adding up to 8 to 20 treatment days per year. Compared to patients who were taking a placebo, those taking Cladribine tablets were over 55% less likely to suffer relapse, and 30% less likely to suffer worsening in their disability due to MS. Professor Giovanonni said: "The introduction of an oral therapy, particularly one that has no short term side effects and is as easy to use as

oral Cladribine, will have a major impact on the treatment of MS. "However, the use of this drug as a first line therapy will have to be weighed up against the potential long term risks which have yet to be defined," he added.

www.thelancet.com

WHILE STATINS INCREASE THE RISK OF DIABETES, THE ABSOLUTE RISK IS LOW

meta-analysis of data from 13 statin trials shows that use of statins increases the risk of developing Type 2 diabetes by 9%, but the absolute health risk is low, especially when compared with the benefit of statin therapy for reducing coronary events. Researchers came to these conclusions in an article published in The Lancet online recently. The study was undertaken by Professor Naveed Satar and Dr. David Preiss, Glasgow Cardiovascular Research Centre, University of Glasgow, UK, and colleagues. As background, the authors noted that trials involving statins have produced conflicting results about an increased risk of the development of diabetes. To resolve this uncertainty, the authors conduct the metaanalysis of published and unpublished data in order to identify any correlation between statin use and development of diabetes. They included 13 trials from the period 19942009, and each trial enrolled over 1,000 patients, with identical follow-up in both the statin and nonstatin groups and a duration of more than 1 year. Trials of patients with organ transplants, or in need of dialysis, were excluded. The 13 statin trials included a total of 91,140 subjects, and 4,278 (2,226 assigned statins and 2,052 assigned control therapy) developed diabetes over an average of 4 years. The investigators reported that statin therapy associated with a 9% increased risk for developing diabetes, with consistency in risk

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across the trials. Sub-analyses revealed that the risk of diabetes with statins was higher in trials with older participants. Notably, neither baseline body-mass index (BMI) nor change in LDL cholesterol appear to influence the statinassociated risk of developing diabetes. Translated into clinical terms, treatment of 255 patients with statins for 4 years resulted in one extra case of diabetes. The authors emphasised that their findings do not prove that statin therapy raises diabetes risk through a direct molecular mechanism; they suggest that this possibility needs further study. However, they conclude that it is unlikely that the increased diabetes risk in those using statins is be a chance finding. The authors also emphasised that treatment of 255 patients with statins for 4 years would give one extra case of diabetes, but that for1mmol/L reduction in LDL (bad) cholesterol concentrations (caused by statin therapy) the same 255 patients could expect to experience five less major coronary events (coronary heart disease death or non-fatal heart attack). They noted that it could be useful to monitor older people receiving statin therapy for development of diabetes since they appear to be more at risk. “We recommend that development of diabetes is specified as a secondary endpoint in future large endpoint statin trials, and suggest that, when possible, reports of long-term follow-up in existing trials should also include incident diabetes.” They concluded, “In view of the overwhelming benefit of statins for reduction of cardiovascular events, the small absolute risk for development of diabetes is outweighed by cardiovascular benefit in the short and medium term in individuals for whom statin therapy is recommended. We therefore suggest that clinical practice for statin therapy does not need to change for patients with moderate or high cardiovascular risk or existing cardiovascular disease. However, the potentially raised diabetes risk should be taken into account if

statin therapy is considered for patients at low cardiovascular risk or patient groups in which cardiovascular benefit has not been proven.”

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

OBESE TEENS ACHIEVE SIGNIFICANT WEIGHT LOSS WITH GASTRIC BANDING

ompared to severely obese adolescents in an intensive lifestyle management programme, a higher percentage of such teens who received laparoscopic adjustable gastric banding lost more than 50% of excess weight and experienced greater benefits to health and quality of life, according to a study in the recent issue of the Journal of the American Medical Association (JAMA). As background, the authors noted that, in the U.S., more than 17.4%, or more than 5 million adolescents, were obese in 2004, an increase from 14.8% in 2000. And lifestyle programmes that include changes in diet, exercise, and behaviour to promote weight loss often produce poor results. “Bariatric surgery is now extensively used for adults and is being evaluated for adolescents,” the authors wrote. “Laparoscopic adjustable gastric banding (gastric banding) has the potential to provide a safe and effective treatment.” Paul E. O’Brien, M.D., F.R.A.C.S., and colleagues of Monash University and the Centre for Adolescent Health, Royal Children's Hospital, Melbourne, Australia, conducted the comparative study. They randomised 50 adolescents between 14 and 18 years of age with a body mass index (BMI) higher than 35 to either participate in a supervised lifestyle intervention or to undergo gastric banding. The subjects were followed for 2 years. The lifestyle intervention programme included reduced calorie intake, increased activity and behavioural modification. The study took place between May 2005 and September 2008. Twenty-four of 25 patients in the gastric banding group and 18 of 25 in the lifestyle group completed the study. The investigators reported that the primary outcome of greater than 50% of excess weight loss was achieved by 21 of 25 participants (84%) in the gastric banding group and 3 of 25

(12%) in the lifestyle group. Notably, at 2 years the gastric banding group had lost an average of about 76 lbs., representing an overall average loss of 28.3% of total body weight and 78.8% excess weight loss. The lifestyle group lost an average of 6.6 lbs., an average 3.1% total weight loss and 13.2% excess weight loss. The differences between groups was significant for all weight measures at 24 months. “At entry, 9 participants (36%) in the gastric banding group and 10 (40%) in the lifestyle group had the metabolic syndrome. At 24 months, none of the gastric banding group had the metabolic syndrome compared with 4 of the 18 completers (22%) in the lifestyle group,” the authors said. The gastric banding group experienced improved quality of life with no adverse events in the period shortly after surgery. However, 8 operations (33%) involving revisional procedures were required in 7 patients in the surgery group. The researchers concluded, “In this study, gastric banding proved to be an effective intervention leading to a substantial and durable reduction in obesity and to better health. The adolescent and parents must understand the importance of careful adherence to recommended eating behaviours and of seeking early consultation if symptoms of reflux, heartburn, or vomiting occur. As importantly, they should be in a setting in which they can maintain contact with health professionals who understand the process of care. This study indicates that, in such a setting, the laparoscopic adjustable gastric banding process can achieve important improvements in weight, health, and quality of life in severely obese adolescents.”

BMJ British Medical Journal www.bmj.org

PAROXITINE INHIBITS THE BENEFITS OF TAMOXIFEN IN BREAST CANCER

omen with breast cancer who take tamoxifen and the antidepressant paroxetine at the same time have at an increased risk of death, researchers reported recently in the British Medical Journal (BMJ). But the investigators stressed that their findings should not lead patients to stop taking tamoxifen, and should also not lead to a conclusion that paroxetine itself causes or

influences the course of breast cancer. "This is simply a situation in which paroxetine impairs the effectiveness of tamoxifen," they said. As background, the authors noted that tamoxifen must be converted into an active metabolite (endoxifen) by the liver, and some drugs can interfere with this process. Though many antidepressants have little or no impact on tamoxifen's metabolism, paroxetine, an SSRI (selective serotonin reuptake inhibitor), inhibits the metabolic step that converts tamoxifen to endoxifen. In this study, Dr. Catherine Kelly and colleagues at the Institute for Clinical Evaluative Sciences (ICES) in Toronto, Ontario investigated retrospectively whether SSRIs can reduce tamoxifen's effectiveness in clinical practice. They analysed healthcare records of 2,430 women aged 66 years or older with breast cancer who received tamoxifen between 1993 and 2005. About 30% of these subjects received an antidepressant at some point during their tamoxifen treatment. Paroxetine was the most commonly used antidepressant. The investigators found that paroxetine use, but not use of other SSRIs, in combination with tamoxifen, was associated with an increased long-term risk of breast cancer death. They concluded that this finding supports the theory that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer. The researchers estimate that paroxetine treatment for 41% of the total time of tamoxifen treatment (the median in this study) will result in one additional breast cancer death at five years for every 20 women so treated. And they also found that the risk of death increased with longer overlapping use of the drugs. "Our findings indicate that the choice of antidepressant can significantly influence survival in women receiving tamoxifen for breast cancer," said Dr. David Juurlink, a coauthor and a scientist at ICES. "This observation is consistent with what we know about tamoxifen's metabolism. These results highlight a drug interaction that is extremely common, widely underappreciated and potentially lifethreatening, yet uniformly avoidable." "Tamoxifen is a crucial element of therapy for patients with hormone receptor-positive breast cancer regardless of age or breast cancer stage," Dr. Jurlink added. "When coprescription of tamoxifen with an antidepressant is necessary, preference should be given to antidepressants that exhibit little or no impact on tamoxifen's metabolism."

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FDA Highlights - by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs ARB USE ASSOCIATED WITH REDUCED RISK OF ALZHEIMER'S

n a recent issue of the British Medical Journal, researchers reported that angiotensin receptor blockers (ARBs) were associated with a significant decrease in the occurrence and progression of dementia. Investigators from the Boston University School of Medicine, Boston, Massachusetts, analysed data from the Decision Support System Database of the US Department of Health System Veterans Affairs (including over 5 million subjects). They compared patients who used ARBs with persons of a similar health status who were taking different medications. They found that patients taking ARBs achieved a 50% reduction in the risk of developing Alzheimer's disease or dementia. Patients taking 2 forms of medications targeting the angiotensin system, ARBs and Angiotensin Converting Enzyme (ACE) inhibitors, achieved a 55% lower risk of

developing dementia. The investigators also studied data on patients already diagnosed with Alzheimer's disease or dementia, and found that such patients had up to a 67% lower chance of being admitted to nursing homes or dying if they were taking both ARBs and ACE inhibitors. "For those who already have dementia, use of ARBs might delay deterioration of brain function and help keep patients out of nursing homes," said senior author Benjamin Wolozin, MD, of Boston University School of Medicine. "The study is particularly interesting because we compared the effects of ARBs with other medications used for treating blood pressure or cardiovascular disease. This suggests that ARBs are more effective than other blood pressure and cardiovascular medications for preventing Alzheimer's disease or dementia." It is unclear exactly why ARBs might be so beneficial, the authors noted.

For those who already have dementia, use of ARBs might delay deterioration of brain function and help keep patients out of nursing homes

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

PROGESTERONE TREATMENT OPTION FOR TRAUMATIC BRAIN INJURIES

rogesterone should be considered as an option for treating traumatic brain injuries, researchers report in a Clinical Perspective published in the recent issue of the American Journal of Roentgenology. "Traumatic brain injury is an important clinical problem in the United States and around the world," said lead author Donald G. Stein, PhD, Emory University, Atlanta, Georgia. "Traumatic brain injury has received more attention recently because of its high incidence among combat casualties in Iraq and Afghanistan," he continued. "Current Department of Defense statistics indicated that as many as 30% of wounded soldiers seen at Walter Reed Army Hospital have suffered a TBI, a finding that has stimulated government interest in developing a safe and effective treatment for this complex disorder." "Growing evidence indicates that post-injury administration of progesterone in a variety of brain damage models can have beneficial effects, leading to substantial and sustained improvements in brain functionality," said Dr. Stein. "Progesterone given to both males and females can cross the blood-brain barrier and reduce oedema levels after; in different models of cerebral ischaemia, significantly reduce the area of necrotic cell death and improve behavioural outcomes; and protect neurons distal to the injury that would normally die," added Dr. Stein. Progesterone was recently tested in two phase 2 clinical trials for traumatic brain injury, leading to the comments in this Clinical Perspective . A phase 3 trial begins soon. "Given its relatively high safety profile, its ease of administration, its low cost and ready availability, progesterone should be considered a viable treatment option - especially because, in brain injury, so little else is currently available," said Dr. Stein.

INTENSIVE INSULIN THERAPY IN SEPTIC SHOCK PATIENTS

se of intensive insulin therapy to counter elevated blood glucose in adults treated with corticosteroids who experience septic shock does not result in a reduced risk of in-hospital death, compared with patients who receive conventional insulin therapy. Researchers reported this finding in the recent issue of The Journal of the American Medical Association, (JAMA).

‘

Patients treated with intensive insulin had significantly more episodes of severe

hypoglycemia than those in the conventional

’

treatment group.

The investigators also reported that adding a 2nd corticosteroid to treatment did not significantly reduce the risk of in-hospital death. Djillali Annane, MD, Hôpital Raymond Poincaré, Garches, France, and colleagues with the Corticosteroids and Intensive Insulin Therapy for Septic Shock (COIITSS) trial studied whether normalisation of blood glucose levels with intensive insulin treatment would improve outcomes for adults with septic shock treated with hydrocortisone. They also studied the benefit of adding fludrocortisone to hydrocortisone therapy. The randomised trial included 509 adults with septic shock who had received hydrocortisone treatment. It was conducted from January 2006 to January 2009 in 11 intensive care units in France. Patients were randomised to 1 of 4 groups: continuous intravenous insulin infusion with hydrocortisone alone; continuous intravenous insulin infusion with hydrocortisone plus fludrocortisone; conventional insulin therapy

with hydrocortisone alone; or conventional insulin therapy with intravenous hydrocortisone plus fludrocortisone. Hydrocortisone was administered every 6 hours, and fludrocortisone was administered once a day for 7 days. They researchers reported that, at time of hospital discharge, 117 of 255 patients (45.9%) treated with intensive insulin therapy had died, and 109 of 254 patients (42.9%) treated with conventional insulin therapy had died. They noted that patients treated with intensive insulin had significantly more episodes of severe hypoglycemia than those in the conventional treatment group. The investigators also reported that, at hospital discharge, 42.9% of the patients in the fludrocortisone-treated group died and 45.8% of patients in the conventional insulin therapy group had died. "No significant difference in overall mortality existed between the fludrocortisone-treated patients and the controls," the authors wrote. "Nor did significant differences exist between the 2 groups for the survivors' ICU and hospital lengths of stay, for the number of vasopressor-free days, and for mechanical ventilation-free days." "The current study showed no evidence to support a strategy of intensive insulin therapy aimed at maintaining blood glucose levels in the range of 80 to 110mg/dL for treating septic shock with corticosteroids," they wrote. "The current data do not support the routine use of oral fludrocortisone in addition to hydrocortisone when physicians decide to introduce corticosteroids in the management of a patient with septic shock."

ESCITALOPRAM MIGHT IMPROVE POST-STROKE COGNITIVE FUNCTION

atients treated with the antidepressant escitalopram following a stroke appear to have greater improvements in thinking, learning, and memory skills than those taking placebo or participating in problem-solving therapy, researchers reported in the recent issue of Archives of General Psychiatry. "…Besides the efforts currently undertaken to increase the number of patients treated with thrombolytic agents, there is growing interest in

restorative therapies that can be administered during the first few months after stroke, the period within which we observe the greatest degree of spontaneous recovery of initial motor and cognitive deficits," the authors wrote. They hypothesised that antidepressants could be effective because of their ability to stimulate production of compounds essential for nerve cell growth. Ricardo E. Jorge, MD, University of Iowa, Iowa City, Iowa, and colleagues studied the effects of escitalopram treatment on 129 stroke patients. Within 3 months of their stroke, 43 patients were randomised to 5 to 10 mg of escitalopram daily and 45 were randomised to daily placebo daily; 41 were randomised a problem-solving therapy program developed for treating patients with depression. After 12 weeks of treatment, patients taking escitalopram achieved higher scores on tests assessing overall cognitive function and measuring verbal and visual memory. "Importantly, the reported changes in neuropsychological performance resulted in an improvement in related activities of daily living," the authors noted. "The beneficial effect of escitalopram on cognitive recovery was independent of its effect on depressive symptoms and was not influenced by stroke type or mechanism of ischaemic stroke," they continued. "In addition, escitalopram was well tolerated and the frequency of adverse effects related to its administration was not different than that observed among patients receiving placebo." A growing body of evidence suggests that antidepressants cause changes in brain structure, including the visual cortex, hippocampus, and cerebral cortex, the authors noted. "Overall, whatever may be the mechanism of improved cognitive recovery, this study has shown, for the first time, that escitalopram is associated with improved cognitive recovery following stroke compared with placebo and Problem-Solving Therapy," they concluded. "The utility of antidepressants in the process of post-stroke recovery deserves to be further investigated." Sources: Boston University Medical Center, American Roentgen Ray Society, JAMA, Archives of General Psychiatry.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

by Steve Devrell

Only the weak survive

View from The Waiting Room

ne of the fascinating things about writing is that it allows you to deviate and I have just deviated! Originally, I was researching the increasing use of inhalers in our society to combat the rise in cases of Asthma. Then I became fascinated by the number of famous historical and contemporary figures who have overcome various degrees of impairments to make their substantial mark in the world. Asthma has had some pretty illustrious sufferers including Bob Hope, Alice Cooper, Elizabeth Taylor and Che Guevara. Incredibly, it became almost a pre-requisite for US Presidents to be asthmatic. The 26th (Theodore Roosevelt,) 28th (Woodrow Wilson,) 30th (Calvin Coolidge,) and the 35th (JFK) all suffered from the condition. Kennedy made great efforts to hide his disability as he believed that admitting to it would be a sign of weakness on the tough political stage. Ever since David Beckham was spotted on the touchline, wheezing into his inhaler, he has become almost a role model for suffers of asthma. But he is not the only famous sportsman to have lived with the condition. Sir Chris Boardman, the double gold medal winning Olympic cyclist, Jim Ryan the 1500 metres world record holder and heptathlete Jackie Joyner-Kersee, reputed to be the greatest female athlete of all time are all asthmatic. Poor Mr Beckham is not only asthmatic; he also suffers from Obsessive Compulsive Disorder. It is reported that his OCD manifests itself through constant cleanliness and perfection. Anything out of order causes a conflict and must be attended to immediately. Famously, it has been reported that he can only have pairs of objects like two, four or six cans in the fridge, odd numbers cannot be tolerated. DB is in quite exalted company with his OCD. Howard Hughes was a fellow suffer and so too, is Donald Trump; the latter’s fear of germs means he refuses to touch the ground floor button of a lift and he avoids shaking hands with people.

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

Albert Einstein, one of the greatest minds of the twentieth century also sadly suffered from OCD. He was also autistic and dyslexic. He really had an awful memory for the simplest of things. Although he succeeded in solving some of the most complicated mathematical formulae with little trouble, he could not remember the months of the year and he never learned how to tie up his shoelaces properly. Many famous, successful and gifted individuals have battled with dyslexia which gave them a particularly torrid childhood as they struggled with this little understood condition. It is only in recent times that the condition has been better diagnosed and indeed recognised. Incredibly, some of the world’s most successful authors, including Agatha Christie and Hans Christian Anderson were dyslexic. Other notable dyslexics include Alexander Graham Bell, Thomas Edison and Richard Branson, who described his schooldays as something of a nightmare. In the world of entertainment, Cher, Tom Cruise, Whoopi Goldberg and Walt Disney all suffered from dyslexia. The more physical condition of epilepsy has plagued many famous names in of the past and present. Julius Caesar, Alfred the Great suffered from epilepsy as did George Frederick Handel and Lewis Carrol. The latter described his epileptic attacks as being like the sensation of falling in hole and everything around getting smaller or bigger. In more modern times, Richard Burton was crippled all his life by epilepsy and became a heavy drinker in order to try and prevent the seizures. Eventually this led to a depression, but he had a paranoiac mistrust of doctors and never once went to see one! Perhaps less surprisingly is the number of public figures who suffer from some form of mood disorder. Their somewhat unreal and closely scrutinised existence demands a mental strength that many have found difficult to sustain. Stephen Fry and Jaws star Richard Dreyfus are both self confessed manic depressives. Singer Billy Joel has had a lifelong

battle against depression and has tried to take his own life by drinking furniture polish. Boris Yeltsin suffered from severe depression and he used drinking as a way to reduce his anxiety. He often disappeared without warning from official engagements or failed to turn up altogether. Two of the greatest leaders of modern history, namely Sir Winston Churchill and Abraham Lincoln suffered from depression. Indeed Lincoln is thought to have suffered a complete mental breakdown before his election in 1861. Nevertheless, Churchill went on to be voted the greatest Briton of all time and Lincoln was voted into the top three presidents of the USA. Other famous people who suffered from challenging conditions include H. G. Wells. Peggy Lee and Sir Steve Redgrave who were or are diabetics. Donald Sutherland, Arthur C Clarke, Jack Nicklaus, Kerry Packer and Franklin D Roosevelt suffered from polio. Noel Gallagher, Bruce Willis, Tiger Woods, Julia Roberts, Rowan Atkinson and King George VI all suffered some speech impediment or stutter. But those mentioned so far may consider themselves fortunate when compared with my two prize winners (if that is not a too inappropriate term) for overcoming the most disabilities in order to take their rightful places in history’s hall of fame. Ludwig Van Beethoven, arguably the greatest classical composer of all time had more than his fair share of disabilities to overcome. Even before his decline into deafness, he was a manic depressive with little time for anything other than his music. He was also a chronic asthmatic. But of course his greatest and almost unbelievable achievement was to continue composing when he was deaf. For the last thirty years of his life he had to compose almost entirely from memory, yet he said the most difficult

thing he had to deal with through his deafness was his inability to hear the applause of an appreciative audience. My other prize winner must be Horatio Lord Nelson, the great British Admiral and popular hero. In a history book of almost one hundred years ago, Horatio Nelson was described as being a feeble child who joined his uncle at sea at the age of 14. Nelson lost the sight in his right eye, contracted malaria and had his right arm amputated after his elbow had been shattered in battle. In 1805, he succumbed to a heroic death at the Battle of Trafalgar. But what for me is most amazing about Nelson was that he was a chronic

Albert Einstein, one of the greatest minds of the twentieth century

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Peter badge for collecting milk bottle tops for their blind dog appeal. Hardly earth shattering stuff. Conversely, my dear wife, who was a county hockey player, lost the sight in her right eye after an accident when she was twenty. Her career ambitions, (she wanted to teach PE and Games), had to be suddenly changed. But her accident seemed to provide her with a greater incentive to succeed and she went on to become a much respected Head teacher. I am sure the will to succeed becomes greater after an accident or disability. Whether it is the desire to prove people wrong, or it gives further incentive to make the most of the talents available, whilst putting aside the inconvenience of the disability, it is hard to say. What is clear however is that many famous severely disabled individuals succeeded not only to survive against the odds but have contributed greatly to society and in so doing managed to enter the pages of our encyclopaedias.

Albert Einstein, one of the greatest minds of the

twentieth century also sadly suffered from OCD.

He was also autistic and dyslexic. He really had an awful

memory for the simplest of things. Although he succeeded in solving some of the most complicated mathematical

formulae with little trouble, he could not remember the months of the year and he never learned how to

’

tie up his shoelaces properly.

sufferer of sea sickness, a condition that would remain within throughout his illustrious naval career. Now anyone who had ever suffered that churning helpless feeling of sea-sickness must agree with my accolade. For someone like me who (touch wood) has yet to contract anything more serious than nappy rash, it is a sobering thought. My achievements to date are also fairly meagre. A twenty-five yards breast stroke certificate from Beau Street swimming baths and a Blue

Steve Devrell is a semi-retired Deputy Headteacher. He also contributes regularly for many local and national publications. steve@devrell51313.fsnet.co.uk

EVIDENTIA • VOLUME 4 • ISSUE 2 • MARCH/APRIL 2010

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Prescribing Information (Please refer to the full Summary of Product Characteristics before prescribing) Avamys®▼ Nasal Spray Suspension (fluticasone furoate 27.5 micrograms /metered spray) Uses: Treatment of symptoms of allergic rhinitis in adults and children aged 6 years and over. Dosage and Administration: For intranasal use only. Adults: Two sprays per nostril once daily (total daily dose, 110 micrograms). Once symptoms controlled, use maintenance dose of one spray per nostril once daily (total daily dose, 55 micrograms). Reduce to lowest dose at which effective control of symptoms is maintained. Children aged 6 to 11 years: One spray per nostril once daily (total daily dose, 55 micrograms). If patient is not adequately responding, increase daily dose to 110 micrograms (two sprays per nostril, once daily) and reduce back down to 55 microgram daily dose once control is achieved. Contraindication: Hypersensitivity to active substance or excipients. Side Effects: Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. Very common: epistaxis. Epistaxis was generally mild to moderate, with incidences in adults and adolescents higher in longer-term use (more than 6 weeks). Common: nasal ulceration. Rare: hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria. Precautions: Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. Consider additional systemic corticosteroid cover during periods of stress or elective surgery. Caution when prescribing concurrently with other corticosteroids. Growth retardation has been reported in children receiving some nasal corticosteroids at licensed doses. Monitor height of children. Consider referring to a paediatric specialist. May cause irritation of the nasal mucosa. Caution when treating patients with severe liver disease, systemic exposure likely to be increased. Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma and/or cataracts. Pregnancy

and Lactation: No adequate data available. Recommended nasal doses result in minimal systemic exposure. It is unknown if fluticasone furoate nasal spray is excreted in breast milk. Only use if the expected benefits to the mother outweigh the possible risks to the foetus or child. Drug interactions: Caution is recommended when co-administering with inhibitors of the cytochrome P450 3A4 system, e.g. ketoconazole and ritonavir. Presentation and Basic NHS cost: Avamys Nasal Spray Suspension: 120 sprays: £6.44 Marketing Authorisation Number: EU/1/07/434/003 Legal category: POM. PL holder: Glaxo Group Ltd, Greenford, Middlesex, UB6 0NN, United Kingdom. Last date of revision: January 2010

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.

sensitized to mountain cedar pollen. Curr Med Res Opin 2009; 25(6): 1393-1401. 4. Vasar M, Houle P, Douglass J et al. Fluticasone furoate nasal spray: effective monotherapy for symptoms of perennial allergic rhinitis in adults/adolescents. Allergy Asthma Proc 2008; 29: 313-321. 5. Avamys Summary of Product Characteristics 2010. 6. Berger WE, Godfrey JW, Slater AL. Intranasal corticosteroids: the development of a drug delivery device for fluticasone furoate as a potential step toward improved compliance. Expert Opin Drug Deliv 2007; 4(6): 689–701. 7. Berger W, Godfrey JW, Grant AC et al. Fluticasone furoate (FF) nasal spray – development of a next–generation delivery system for allergic rhinitis. J Allergy Clin Immunol 2007; 119(1 Suppl): S231. 8. Godfrey JW, Grant AC, Slater AL. Fluticasone furoate (FF) nasal spray – ergonomic considerations for a next generation delivery system. J Allergy Clin Immunol 2007; 119(1 Suppl): S230. © GlaxoSmithKline group of companies 2010.

Avamys® is a registered trademark of the GlaxoSmithKline group of companies. Code: UK/FF/0008/10 Date of preparation: February 2010 References: 1. Fokkens WJ, Jogi R, Reinartz S et al. Once daily fluticasone furoate nasal spray is effective in seasonal allergic rhinitis caused by grass pollen. Allergy 2007; 62: 1078-1084. 2. Kaiser HB, Naclerio RM, Given J et al. Fluticasone furoate nasal spray: a single treatment option for the symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol 2007; 119(6): 1430-1437. 3. Jacobs R, Martin B, Hampel F et al. Effectiveness of fluticasone furoate 110µg once daily in the treatment of nasal and ocular symptoms of seasonal allergic rhinitis in adults and adolescents