Evidentia Iss4

Volume 4 Issue 4 July/August 2010 ISSN 1753-464X

Conference reports from: Berlin, Chicago, Oslo and New Orleans

LET’S THINK

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

BOEHRINGER INGELHEIM LTD, ELLESFIELD AVENUE, BRACKNELL, BERKSHIRE RG12 8YS TEL: +44 (0) 1344 424600 · FAX: +44 (0) 1344 741444 · WWW.BOEHRINGER-INGELHEIM.CO.UK JOB NO: ONC0107 · DATE OF PREPARATION: MAY 2010

Bringing clinical evidence to practice in primary and secondary care

CONTENTS 4

Guest Editorial - ASCO 2010 by Dr. Denis Talbot

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Pulmonary rehabilitation effective for both obese and slim COPD patients Reporting from the American Thoracic Society annual meeting, New Orleans

COVER STORY

12 Carers for the chronically ill at high risk for IBS Reporting from the Digestive Disease Week 2010 meeting, New Orleans

15 Update on trial results revealed at ESH Reports from the European Society of Hypertension scientific meeting, Oslo

19 Smoking cessation treatments work and are safe for people with severe mental illness - Smoking Cessation report

22 Mental Illness linked to tobacco exposure in womb Report from the American Psychiatric Association annual meeting, New Orleans

9 Children with

23 EMA Highlights - Emerging uses of EMA approved drugs

severe asthma at increased risk of developing COPD

24 Highlights from ASCO annual meeting Reports from the American Society of Clinical Oncology, Chicago

26 Margarine, processed meats and other foods can increase the risk of multiple sclerosis Reports from the European Neurological Society annual meeting, Berlin

28 The BIG FOUR - Reporting from some of the latest journal articles 19

30 World Health Matters - Medical news from around the world 32 FDA Highlights - Emerging uses of FDA-approved drugs 34 View from The Waiting Room - Breast cancer - A personal view 10

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Guest Editorial Dr. Denis Talbot, Consultant Medical Oncologist at the University of Oxford Medical Oncology Department, Churchill Hospital, Oxford

ASCO 2010

R

esults of early clinical trials of agents targeting c-MET were presented at the 46th annual ASCO meeting held in Chicago on June 4th-8th. The c-MET receptor tyrosine kinase (RTK) is the only high affinity cell surface receptor for hepatocyte growth factor and is important in tumour proliferation, motility and invasion. Receptor activation induces growth through RAS-MAPK signalling and apoptosis is inhibited via the PI3 kinase /AKT pathway.

C-MET gene amplification in NSCLC is associated with resistance to EGFR TKIs and a poorer prognosis making it an attractive target for cancer therapy. Several small molecule RTK inhibitors directed against cMET are in development. As RAS signalling is a key factor in the activity of agents targeting c-MET and other RTKs it was topical to have RAS as the focus of the keynote Science of Oncology Award Lecture delivered by Dr. Frank McCormick this year.

The selective c-MET inhibitor, ARQ 197, exhibits synergy with EGFR TKIs in pre-clinical models. This provided the rationale for the design of a randomised clinical trial comparing erlotinib + placebo versus erlotinib + ARQ 197 in patients with NSCLC who had received at least one prior chemotherapy regimen. Schiller (Abstract No. 7502) presented the results of a randomised double blind study that enrolled 167 patients.

ARQ 197 significantly prolonged progression-free survival (PFS) by 6.4 weeks when added to erlotinib, although the 7.2-week difference in overall survival (OS) observed between the two arms did not reach statistical significance. When analyses were performed for patients with nonsquamous histology, a 9.2-week increase in PFS was seen (HR=0.61; p<0.05) and OS improved by 13.7 weeks in the combination arm (HR=0.58; p<0.05). It was reported that patients with KRAS mutant disease were more likely to derive PFS advantage following ARQ 197 therapy.

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

Treatment related adverse events, mostly rash and diarrhoea were similar in both arms of the study.

Further assessment of potential predictive biomarkers will be important in the future development of this agent.

One of the most exciting discoveries in recent years was the identification in 2007 that a translocation or inversion within chromosome 2p results in the formation of a fusion gene product comprising portions of the echinoderm microtubule associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene.

‘

ELM4-ALK is expressed in only 3.5% of patients with NSCLC, predominantly in younger males with adenocarcinoma who are light or never smokers.

’

Several variants of EML4-ALK fusion proteins are known to be catalytically active kinases with potent transforming and oncogenenic properties in pre-clinical lung cancer models. ELM4-ALK is expressed in only 3.5% of patients with NSCLC, predominantly younger males with adenocarcinoma who are light or never smokers.

However, EML4-ALK is rarely coincident with EGFR or KRAS mutations. ALK selective inhibitors have been developed and shown to be highly effective in NSCLC xenograft models that harbor ELM4-ALK rearrangements. Just three years after the initial discovery, the first clinical trial of an ELM4-ALK targeted drug has been completed probably a record for the time from target identification to clinical application. The results of

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

the phase II study of the oral ALK and c-MET inhibitor crizotinib (PF2341066) in patients with ALK positive NSCLC was presented by Bang (Abstract No. 3). Eighty-two heavily pre-treated patients with NSCLC (96% adenocarcinomas) who had ELM4-ALK FISH positive tumours were enrolled into an open label study of single agent crizotinib at a dose of 250mg twice daily.

Consistent with the phase I data, the drug was well tolerated. Grade 4 ALT occurred in 1% patients; Grade 3 rises in ALT and AST was observed in 12% patients; Grade 1 nausea, diarrhoea and vomiting were experienced by 50% of patients. As recorded in earlier studies, 42% patients experienced abnormalities in visual accommodation. The waterfall plot was very impressive. Objective responses occurred in 57% (CI 46-68%) patients with one patient achieving a complete response. Although the median follow up was 6.4 months, the PFS had not been reached with 72% of patients alive six months after commencing crizotinib treatment. The result of the randomised phase III (PROFILE) trial in the second-line setting is eagerly awaited.

What of other news? The insulin growth factor receptor (IGFR1) is recognised as a valid target for therapy of NSCLC. There are a number of agents in development, both small molecule RTK inhibitors and antibodies, reported at ASCO. Results of the phase III study of the humanised IgG2 monoclonal antibody figitumumab directed against the IGFR1 was presented by Jassem (Abstract No. 7500). The first-line study in nonadenocarcinoma randomised to carboplatin ± figitumumab closed early after accrual of 681 patients because of excess toxicity in the study arm. Studies of other IGFR1 targeted agents were also reported at earlier stages of development, with small molecular weight inhibitors showing significant promise. In contrast to the sensational results of the IPASS study

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American Thoracic Society - by Samuel Peters Reporting from the ATS annual meeting, New Orleans

Pulmonary rehabilitation effective for both obese and slim COPD patients Obesity doesn’t appear to have a detrimental effect on the benefits gained from pulmonary rehabilitation. Dr. Neil Greening from University Hospital, Leicester presents his findings.

N

early half of carers for chronically ill obese patients with chronic obstructive pulmonary disease (COPD) stand to gain as much from pulmonary rehabilitation (PR) as their slimmer counterparts, even though as a group they have a lower exercise capacity, according to new research from the University Hospitals of Leicester.

"Like the healthy population, the prevalence of obesity is increasing in those with COPD," said Neil Greening, MBBS, MRCP, who led the study.

"There is evidence that obesity may lower exercise capacity but at the same time appears to confer a survival advantage, which is known as the obesity paradox. Pulmonary rehabilitation is effective in improving exercise capacity and health status in COPD but it is unclear whether these benefits accrue in patients with extreme obesity. We wanted to compare the outcomes of a pulmonary rehabilitation programme in

< CONTINUED FROM PAGE 4

presented at ASCO 2009, there were few ground-breaking studies on EGFR targeted agents this year. The randomised NCIC BR.19 trial of adjuvant gefitinib in resected NSCLC was discontinued early because of lack of benefit (Goss, Abstract No. 7005). A randomised comparison of first-line erlotinib with erlotinib + chemotherapy in advanced disease in predominantly white never smokers demonstrated no difference in response rate, PFS or OS presented on behalf of the CALGB by Janne (Abstract No. 7503). The sequence of firstline erlotinib followed by chemotherapy is inferior to chemotherapy followed by erlotinib in advanced disease was the conclusion of the TORCH study presented by Gridelli (Abstract No. 7508). It is anticipated that effective EGFR targeted agents will be developed for treatment of erlotinib and gefitinib resistant disease.

However, it was the c-MET and ALK targeted therapies that stole the show this year at ASCO.

disparity in obese patients with COPD. Obese patients with obesity of varying severity and patients do not have the same improvements in normal weight subjects." health status following pulmonary rehabilitation.

To compare the effects of pulmonary In particular, fatigue does not improve, possibly rehabilitation between obese and non-obese due to co-existing medical problems, such as patients, Dr. Greening and colleagues recruited obstructive sleep apnoea or obesity patients with clinical and spirometric COPD hypoventilation, according to Dr. Greening. and classified them according to their level of However, the most puzzling question remains obesity, from normal weight (BMI 21-25kg/m2) the survival benefit conferred by obesity. "As to extreme obesity (BMI >40 kg/m2). The medical professionals, we know that obesity is patients underwent pulmonary rehabilitation linked with medical complications such as at a single centre in the UK. The improvements diabetes and heart disease, so how it can lead to in their exercise performance and endurance, a survival advantage in other diseases such as as well as their health status (chronic COPD or chronic kidney disease is puzzling. The respiratory questionnaire) and baseline reasons for this are currently unknown and characteristics were assessed. further research is needed."

"We found that obese people with COPD are A larger study is planned to examine some of more disabled in terms of exercise capacity, these issues. "We are planning a study to look at despite having less severe airflow obstruction the underlying mechanisms of skeletal muscle (the measure used to quantify severity of COPD). dysfunction and obesity in COPD," said Dr. However, they do just as well with rehab Greening. "Rather than a larger multi-centre including those with extreme obesity," said Dr. study looking at epidemiology, we are trying to Greening. "There is no difference between understand why obesity affects patients with obesity subgroups in the proportion of patients COPD in the way it does." achieving a clinically significant improvement in the incremental shuttle walk test."

Reference: This is the first study to look at PR in extreme "The Effects of Pulmonary Rehabilitation on Extreme obesity. While the researchers expected to find Obesity in COPD" (Session A27, ATS 2010, 16.5.10, Abstract 1342) that some improvement would be seen after the pulmonary rehabilitation programme, they were surprised to see no difference in training effects between normal weight and extremely obese patients.

"Patients with COPD, irrespective of body mass, improve following a pulmonary rehabilitation programme.

Therefore extremely obese patients with COPD should still be considered for enrolment," said Dr. Greening, adding that although there are no weight limits for pulmonary rehabilitation programmes, there is likely some discrimination by medical staff who may Researchers were surprised to see no difference emphasise weight loss over exercise. in training effects between normal weight and There remain questions about the extremely obese patients E V I D E N T I A • V O L U M E 4 • I S S U E 4 • J U LY / AU G U S T 2 0 1 0

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American Thoracic Society - by Samuel Peters Reporting from the ATS annual meeting, New Orleans

Internet monitoring strategy for severe asthma patients shown to be effective Internet support and daily monitoring of exhaled nitric acid appear to reduce need for oral corticosteroids in patients with severe asthma according to Dr. Simone Hashimoto, research fellow from the department of respiratory medicine of the University of Amsterdam.

P

atients with severe asthma who use an internet-supported strategy and daily monitoring of exhaled nitric oxide (FENO) were able to control their asthma with lower overall dosing of oral corticosteroids (OCS) than patients who underwent usual care, according to research from the Netherlands.

‘

Since adverse effects

are dose and time dependent, corticosteroids should always be

used in the lowest

’

possible dose.

"We know that in patients with prednisonedependent asthma it is important to adjust the daily dose of oral corticosteroids to the lowest possible level in order to reduce long-term side effects," said Simone Hashimoto, M.D., research fellow from the department of respiratory medicine of the University of Amsterdam. "Our study shows that a novel internet-supported strategy including daily measurements of an objective marker of airway inflammation, FENO, and supervision by an asthma nurse allows frequent adjustments of prednisone dose, and leads to significant reduction of total corticosteroid consumption over a six month study period, as compared with patients receiving usual care. This was not accompanied by deterioration of asthma control or asthmarelated quality of life."

The findings were presented at the ATS 2010 International Conference in New Orleans.

People with chronic health conditions, such as severe asthma, require continuous medical

6

lung function, FENO, and regular feedback by an supervision, which can often be a logistical internet asthma nurse, would lead to a challenge, not only for overburdened significant reduction of corticosteroid healthcare systems, but for patients themselves, consumption without worsening of asthma who may not have the time or flexibility to keep control or asthma-related quality of life. In total, frequent appointments. "Internet monitoring 89 patients were randomised to two tapering allows centralised continuous long-distance strategies: usual care, or internet-supported with support of patients, which can improve the daily monitoring of FENO, FEV1 and symptoms. quality of care, reduce the hazards associated For those assigned to the internet-supported with oral corticosteroids tapering, and can strategy, each patient had a password used to prevent drug-induced morbidity and mortality," log in to a secure site where they recorded daily explained Dr. Hashimoto. symptoms, lung function values, FENO value and While it was known that in patients with milder dose of medicine that they took in the day. The asthma, such programmes had shown success, values were controlled every day by a specialised patients with severe asthma had to be studied. asthma nurse and once a week patients received "Some patients with severe asthma require instructions about the dose of oral corticosteroids frequent bursts or even daily use of oral they should use. The process took about five corticosteroids despite treatment with high minutes per day for the patient, and was well doses of inhaled asthma medication. This leads accepted. Patients could also contact the asthma to serious long-term adverse effects such as nurse via the website or email in the event of diabetes, blood hypertension, depression and questions or problems. osteoporosis, that may critically affect patients' quality of life and have considerable public CONTINUED ON PAGE 9 > health implications," explained Dr. Hashimoto.

"Since adverse effects are dose and time dependent, corticosteroids should always be used in the lowest possible dose. In current practice, oral corticosteroid dose adjustments are made periodically by the patient's physician, based on subjective symptoms and signs, and not by objective parameters."

Dr. Hashimoto and colleagues designed a prospective, randomised, parallel, multicentre study with 89 patients with severe “Internet monitoring allows centralised continuous longasthma to test the hypothesis distance support of patients, which can improve the quality that a new internet-based of care, reduce the hazards associated with oral strategy including daily home corticosteroids tapering, and can prevent drug-induced monitoring of symptoms, morbidity and mortality”

E V I D E N T I A • V O L U M E 4 • I S S U E 4 • J U LY / AU G U S T 2 0 1 0

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fluticasone furoate

Nasal and ocular symptom relief

Welcome to a world of

allergic rhinitis relief...

Avamys is an intranasal steroid providing relief from both nasal and ocular allergic rhinitis symptoms.1-4 It’s a once daily therapy5 available in an advanced device.6-8

Not actual size

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

American Thoracic Society - by Samuel Peters Reporting from the ATS annual meeting, New Orleans

Children with severe asthma at increased risk of developing COPD Worrying figures show 30 times greater risk for asthmatic children to develop adult COPD. Dr. Andrew Tai from the Royal Children’s Hospital, Melbourne presents his study.

C

hildren with severe asthma have more than 30 times the risk of developing adult chronic obstructive lung disease (COPD) as adults compared to

‘

were recruited at the age of seven, from a 1957 birth cohort and were assessed regularly until the age of 50. At recruitment, subjects were classified as having no history of wheeze,

It is important to emphasise that the lung function decline in this group is not increased compared to those with mild or

’

no asthma, as has been raised in some other studies...

children without asthma, according to a prospective longitudinal cohort study from the Royal Children's Hospital in Melbourne.

"There is important epidemiological evidence to suggest that events in childhood that influence lung growth constitute a significant risk for COPD," explained lead author, Andrew Tai, MBBS, FRACP. "The aim of this study was to describe the association between the pattern of childhood asthma and the risk of developing adult COPD in a longitudinal cohort."

Subjects of the Melbourne Asthma Study

intermittent asthma (such as viral-induced wheezing), persistent asthma (in the absence of illness), or severe asthma. Of the surviving members of the original group, 197 answered a detailed questionnaire and underwent lung function testing for the current study.

Subjects who were classified as having severe asthma in childhood had an adjusted risk of COPD of 31.9 times that of children without asthma. Interestingly, children with mild asthma were not at increased risk of developing adult obstructive lung disease.

CONTINUED ON PAGE 10 >

< CONTINUED FROM PAGE 6

The researchers found that among patients assigned to the internet-supported strategy, cumulative six-month dosing of OCS was significantly lower. "Of course, we hoped to find a positive result, because internet based selfmanagement and management guidance by FENO has already been proven to be successful in adolescents with milder forms of asthma," said Dr. Hashimoto. "However, we were surprised that also in patients with severe prednisone-dependent asthma this strategy proved to be successful. These patients have

years of continuous use of oral corticosteroids and a long history of attempts to taper their maintenance prednisone dose without success.

This strategy gives them new hope that they can safely reduce the deleterious long-term side effects of prednisone."

"Our findings suggest that this novel internet-based strategy can and should be applied in all patients with severe prednisone dependent asthma to reduce total corticosteroid consumption. Internet technologies as well as biomarker-driven

therapies will become more and more common in future health care," Dr. Hashimoto concluded. "In the future, we will do more studies on a larger scale, to evaluate whether this strategy should be incorporated in guidelines for management of patients with severe asthma."

Reference: "Monitoring Exhaled Nitric Oxide (FENO) to Tailor the Lowest Effective Dose of Oral Corticosteroids in Severe Asthma (MONOSA- Study)" (Session B92, ATS 2010, 17.5.10, Abstract 492)

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American Thoracic Society - by Samuel Peters Reporting from the ATS annual meeting, New Orleans

Children with severe asthma at increased risk of developing COPD < CONTINUED FROM PAGE 9

‘

"At this stage, children with mild asthma are those who have symptoms of wheeze which are triggered primarily by respiratory infections. A majority of children with mild asthma remit by adolescence or adulthood," explained Dr. Tai. "However, children with more severe asthma features tend to have predisposing risk factors (like atopy) and continue to have symptoms of wheeze well into adult life."

"It is important to emphasise that the lung function decline in this group is not increased compared to those with mild or no asthma, as has been raised in some other studies," Dr. Tai continued. "However, lung function in children with severe asthma is reduced in childhood years and declines in adult life to levels consistent with adult obstructive lung disease. Fundamentally, we believe that this severe asthma group start with a lesser baseline lung function and gradually deteriorate to the levels consistent with a diagnosis of COPD. At this stage, there is no data on when airway remodeling occurs in children and hence, its impact on lung function, but there is an emerging relationship between childhood severe asthma and adult

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Currently, there are

more than 30 birth cohort studies of varying duration being conducted

’

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obstructive lung disease."

Importantly, this study was performed on a group of children recruited in the 1960s when anti-inflammatory treatment was not available.

Studies to date suggest that anti-inflammatory medications do not alter the natural progression of mild childhood asthma, but there are no studies performed in those children with severe asthma.

"There should be greater emphasis on the surveillance and treatment of children with asthma, therefore potentially preventing the development of adult obstructive lung disease," said Dr. Tai.

• • • • • • •

Researchers still do not fully understand the mechanisms that link severe childhood asthma with adult COPD, but these findings suggest that appropriate treatment strategies (and surveillance) should be instigated early in life to potentially minimise future risk.

"Early treatment to prevent airway remodeling in childhood may reduce the incidence of this long-term complication of childhood asthma," concluded Dr. Tai. "Currently, there are more than 30 birth cohort studies of varying duration being conducted around the world. In particular, the long-term follow-up of the Tucson birth cohort into young adulthood has shown trends similar to our findings of airway obstruction originating from early life. Clearly, more research to understand the mechanisms and timing of changes within the airway wall, inflammation and function needs to be conducted, applying preferably non-invasive methods in determining potential contributing factors."

Reference: "Pediatric Origins of Adult Chronic Obstructive Pulmonary Disease (COPD): Childhood Asthma" (Session A95, ATS 2010, 16.5.10, Abstract 2206)

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E V I D E N T I A • V O L U M E 4 • I S S U E 4 • J U LY / AU G U S T 2 0 1 0

Tell me Hubert, how does FOSTAIR

feel?

In between finding change and changing loads, FOSTAIR is there for his asthma.

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

FOSTAIR® ▼ (beclometasone dipropionate and formoterol fumarate dihydrate) pressurised inhalation solution PRESCRIBING INFORMATION (Refer to Summary of Product Characteristics before prescribing).

Presentations: Pressurised inhalation solution containing 100 micrograms of beclometasone dipropionate and 6 micrograms of formoterol fumarate dihydrate per actuation. Indications: Regular treatment of asthma where use of a combination product (inhaled corticosteroid and long-acting beta2-agonist) is appropriate: patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled short-acting beta2-agonist; or patients already adequately controlled on both inhaled corticosteroids and long-acting beta2-agonists. Not appropriate for treatment of acute asthma attacks. Dosage and Administration: For inhalation use only. FOSTAIR is not intended for the initial management of asthma. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of beta2-agonists and/or corticosteroids by individual inhalers should be prescribed. Adults: one or two inhalations twice daily, maximum four inhalations daily. Not recommended for patients under 18 years. Beclometasone dipropionate in FOSTAIR is characterised by an extrafine particle size distribution which results in a more potent effect than formulations of beclometasone dipropionate with a non extra-fine particle size distribution (100 micrograms of beclometasone dipropionate extra-fine in FOSTAIR are equivalent to 250 micrograms of beclometasone dipropionate in a non extra-fine formulation). Therefore the total daily dose of beclometasone dipropionate administered in FOSTAIR should be lower than the total daily dose of beclometasone dipropionate administered in a non extra-fine beclometasone dipropionate formulation. Contraindications: Hypersensitivity to any of the components.

Precautions: Cardiovascular disorders including cardiac arrhythmias, thyrotoxicosis, diabetes mellitus, phaeochromocytoma, untreated hypokalaemia, pulmonary infections (tuberculosis, fungal or viral). FOSTAIR should not be used as the first treatment for asthma, should not be initiated during an exacerbation, or during significantly worsening or acutely deteriorating asthma, and should not be stopped abruptly. If patients find the treatment ineffective medical attention must be sought. Systemic effects of inhaled corticosteroids may occur, particularly at high

doses prescribed for long periods. These effects are much less likely to occur with inhaled than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma.

Titrate to the lowest dose at which effective control of asthma is maintained to minimise systemic effects. Special care is needed in transferring patients from oral steroids. FOSTAIR contains a small amount of ethanol (approximately 7mg per actuation); at normal doses the amount of ethanol is negligible and does not pose a risk to patients. Patients should rinse mouth after inhalation to minimise risk of oropharyngeal candid infection. Drug interactions: Beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes without involvement of the cytochrome p450 system. Avoid beta-blockers (including eye drops). Caution is required when theophylline or other beta-adrenergic drugs are prescribed concomitantly with formoterol. Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, MAOIs and TCAs can prolong the QTc interval and increase the risk of ventricular arrhythmias. In addition, L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance.

Concomitant administration with MAOIs, including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertension. Risk of arrhythmias in patients receiving anaesthesia with halogenated hydrocarbons.

Theoretical potential for interaction in sensitive patients taking disulfiram or metronidazole. Pregnancy and Lactation: No experience. Balance risks with benefits. Side effects: Common: pharyngitis, headache, dysphonia. Uncommon: influenza, oral fungal infection, pharyngeal and oesophageal candidiasis, vaginal candidiasis, gastroenteritis, sinusitis, granulocytopenia, dermatitis allergic, hypokalaemia, hyperglycaemia, restlessness, tremor, dizziness, otosalpingitis, cardiac arrhythmias, hyperaemia, flushing, rhinitis, cough, productive cough, throat irritation, asthmatic crisis, pruritus, rash, hyperhidrosis, diarrhoea, dry mouth, dyspepsia, dysphagia, burning sensation of the lips, nausea, dysgeusia, muscle spasms, myalgia, C-reactive protein increased, platelet count increased, free fatty acids increased, blood insulin increased, blood ketone body increased.

Rare: ventricular extrasystoles, angina pectoris, paradoxical bronchospasm, urticaria, angioneurotic oedema, nephritis, blood pressure increased, blood pressure decreased. Very rare: thrombocytopenia, hypersensitivity reactions,

adrenal suppression, abnormal behaviour, sleep disorder, hallucination, glaucoma, cataract, atrial fibrillation, dyspnoea, exacerbation of asthma, growth retardation in children and adolescents, peripheral oedema, bone density decreased. Legal category: POM. Packs and Prices: FOSTAIR 100/6 (PL08829/0156) £29.32.

Each inhaler contains 120 actuations. Full prescribing information is available from the Marketing authorisation holder: Chiesi Limited, Cheadle Royal Business Park, Highfield, Cheadle, SK8 3GY. Date of preparation: February 2009.

REFERENCES 1. De Backer W, Devolder A, Poli G et al. Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic and COPD patients. J Aerosol Med Pulm Drug Deliv 2010 Jan 29.

2. Selroos O, Pietinalho A, Riska H. Delivery devices for inhaled asthma medication.

Clin Immunother 1996; 6: 273-299.

3. Fabbri LM, Nicolini G, Olivieri D et al. Inhaled beclometasone dipropionate/ formoterol extra-fine fixed combination in the treatment of asthma: evidence and future perspectives. Expert Opin Pharmacother 2008; 9: 479-490.

4. Tulic MK, Hamid Q. New insights into the pathophysiology of the small airways in asthma. Clin Chest Med 2006; 27: 41-52.

5. Huchon G, Magnussen H, Chuchalin A et al. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med 2009; 103: 41-49.

Date of preparation: MAY 2010 | Job code: CHFOS20100292

Adverse events should be reported.

Reporting forms and information can be found at www.yellowcard.gov.uk.

Adverse events should also be reported to Chiesi Limited (address as above).

Tel: 0161 488 5555.

Digestive Disease Week - by Bruce Sylvestor Reporting from the DDW 2010 meeting, New Orleans

Carers for the chronically ill at high risk for IBS

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early half of carers for chronically ill patients suffer from irritable bowel syndrome (IBS), probably as a result of the stress they are under.

Of 96 individuals who had been caring for a chronically ill person for at least six months, 47 met Rome II criteria for IBS, reported Jose RemesTroche, MD, of the University of Veracruz in Mexico. At a press conference and subsequent poster session at the Digestive Disease Week meeting, Remes-Troche also said that the caregivers with IBS were more likely to have high scores on the Zarit Caregiver Burden Interview.

Those with IBS had mean Zarit scores of 69 (SD 26), compared with 40 (SD 16) among caregivers not meeting the Rome II criteria (P=0.0001), he reported. Moreover, the stress can cut both ways, as a separate presentation here indicated intimate partners of IBS patients report their own high stress levels. Reuben Wong, MD, of the University of North Carolina, told attendees that Zarit scores among partners of IBS patients were higher than seen in previous studies for partners of cancer patients, and in the same ballpark as those for dementia patients' partners. Both Remes-Troche and Wong indicated that their respective studies were the first of their kinds. In the Mexican study, Remes-Troche and colleagues administered a variety of standard tests and questionnaires to parents, spouses, or nonfamily members responsible for someone with a serious

chronic illness. About half the patients had kidney failure; the rest had diagnoses such as end-stage diabetes, terminal cancer, or advanced neurological diseases. Most caregivers were women, and the mean age was 44 (SD 14). The mean time of caregiving was 25 months (range six to 228). Among those with IBS, about half were constipation predominant and the

‘

All the medical focus

is on the child or parent or spouse i.e. the person with the

chronic illness...

’

remainder were evenly divided between those with diarrhoeal IBS and those with mixed symptoms. There was no apparent relationship between caregivers' age or the duration of caregiving and the prevalence of IBS in the caregivers. However, Zarit scores, as well as symptoms of anxiety and depression, were significantly greater in those with IBS, RemesTroche said. Zarit scores also correlated

significantly with scores on the IBS Quality of Life index (r=-0.60, P=0.001), indicating that increasing caregiver burden was associated with a greater negative impact from IBS symptoms.

Anxiety scores were positively correlated with caregiver burden (r=0.67, P=0.001). Deborah Proctor, MD, a gastroenterologist at Yale University who moderated the press conference at which Remes-Troche spoke, said the findings were definitely plausible as well as important.

"All the medical focus is on the child or parent or spouse i.e. the person with the chronic illness," she said. "Nobody pays attention to the person who is driving them around to appointments."

Following Wong's presentation, session cochairman Brennan Spiegel, MD, of UCLA, picked up on this theme noting that most patients have a caregiver or partner, he said, clinicians should remember the importance of partners and family carers and that often "we're treating not just one person but two."

Wong reported on a study of 114 couples in which one partner (71% female) had IBS according to Rome III criteria, with a mean relationship duration of 24 years. Using an alternative form of the Zarit scale from that in the Mexican study, Wong and colleagues found mean scores of 21.9 in the partners. He noted that previous studies of partners of cancer CONTINUED ON PAGE 14 >

Prostaglandin D2 in UC

R

esearchers have identified a specific chemical that may trigger remission in patients with the debilitating disease of ulcerative colitis.

The team from the Farncombe Family Digestive Health Research Institute has found that people in long-term remission of ulcerative colitis have elevated levels of the same chemical, prostaglandin D2, which they previously found to be important in promoting healing and maintaining remission of the condition in laboratory rats.

"The levels of prostaglandin D2 were only

12

elevated in those patients in long-term remission, and that suggests it is a key factor in preventing new episodes of ulcerative colitis," said John Wallace, director of the Institute and a professor of medicine for the Michael G. DeGroote School of Medicine.

Ulcerative colitis impacts 100,000 Canadians and millions worldwide, but has an unknown cause and limited treatment options. Most people are never cured, and often require surgical removal of the colon.

The discovery may lead to a new treatment for inflammatory bowel disease which would

E V I D E N T I A • V O L U M E 4 • I S S U E 4 • J U LY / AU G U S T 2 0 1 0

promote production of prostaglandin D2, Wallace said. "It is entirely possible our findings could extend to Crohn's disease as well."

The study by Wallace and post doctoral student Linda Vong with colleagues from the University of Calgary is being published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS) on June 14.

Funding for the research was provided by the Canadian Institutes for Health Research and the Crohn's and Colitis Foundation of Canada.

For further information contact: Veronica McGuire vmcguir@mcmaster.ca

Sustained release Colpermin IBS Relief saves its peppermint power ‘til it’s needed

.....

W AIT

....TAKE COLPERMIN ....... .N

O

T

Y . . . . . . ..

ET .... .

.

....

... .....

....

HOLD IT

. . . .. .

G ET READY.. ... !

.

.

.... . ..

EASE NOW REL

... . .

D R IP ... DRIP... DR IP . ....

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.......

Colpermin IBS Relief is the only peppermint oil capsule available with both an enteric coating and a sustained-release formulation, designed to optimise delivery.1,2 So don’t forget to look for MR when prescribing.

Peppermint oil is a logical first-line therapy in IBS because in a meta-analysis of treatments for IBS3 the ‘Number Needed to Treat’ for a successful outcome was 2.5. It was 5 for other antispasmodics.4 Prescribing information can be found overleaf

.

RI DRIP D RIP D

P

Rx Peppermint Oil EC MR 100 0.2 ml

Digestive Disease Week Reporting from the DDW 2010 meeting, New Orleans

Carers for the chronically ill at high risk for IBS < CONTINUED FROM PAGE 12

and dementia patients had yielded average Zarit scores of 18.5 and 32.9, respectively. Wong said that Zarit scores were significantly associated with IBS severity. Partners of those with severe IBS had mean Zarit scores of 27.5, versus 20.5 for moderate IBS and 17.0 for mild illness (P=0.007 for trend). IBS severity did not predict partners' ratings of the quality of sexual relationships. On the other hand, assessments of the strength of the couples' overall relationships were significantly associated with Zarit scores, Wong said. For example, partners were asked how often they regretted getting into the relationship in the first place. Among those who answered "very often" or "constantly," the mean Zarit score was 45.6, compared with 18.8 for those who said "never." Spiegel cautioned that Wong and colleagues drew their sample from a tertiary referral centre for IBS patients, so that the findings might not be generalised to IBSaffected couples seen in general practices. It was suggested that cultural and other differences relating to the amount of family care may change results. Nevertheless, both Proctor and Remes-Troche said, high rates of IBS in the context of severe stress are well known. For example, rates in the 50% range have been reported among individuals with post-traumatic stress disorder, Remes-Troche said.

Prescribing Information Colpermin IBS Relief Capsules Presentation: Sustained release capsules containing peppermint oil 0.2ml Uses: Relief of the symptoms of irritable bowel syndrome. Dosage: Adults and the elderly: One capsule three times a day. Two capsules three times a day in severe discomfort. Children: Not to be used under the age of 15 years. Contraindications: None. Precautions: Swallow capsule whole. Worsening of symptoms may occur in heart burn sufferers; discontinue treatment in these patients. Do not take if allergy to peanuts or soya. Consult a doctor before use in the following circumstances: first presentation of symptoms for confirmation of IBS, aged 40 years or over and some time since last attack, symptoms have changed, blood passed from the bowel, nausea or vomiting, loss of appetite or weight, paleness and tiredness, severe constipation, fever, recent foreign travel, pregnancy or planned pregnancy, abnormal vaginal bleeding or discharge, difficulty or pain in passing urine. If there are new symptoms or worsening of the condition, or failure to improve over two weeks, the patient should consult their doctor. Do not take immediately after food or with indigestion remedies. Pregnancy and lactation: Not recommended. Side effects: Heartburn, perianal irritation. Rarely, allergic reactions incl. rash, headache, bradycardia, muscle tremor and ataxia which may occur when taken with alcohol. NHS cost: 20s: £3.40; 100s: £12.05. Legal cat: GSL. PL holder: McNeil Products Ltd, Maidenhead, Berkshire, SL6 3UG. PL no: 15513/0141.

Date of prep: Feb 2010

Disclosure: Neither study had commercial funding. Wong and Remes-Troche reported no disclosures. Proctor reported relationships with Abbott and Genentech.

Spiegel reported relationships with Amgen, AstraZeneca, Prometheus Laboratories, Rose Pharma, and Takeda.

Rreference: Remes-Troche J, et al. Irritable bowel syndrome (IBS) among caregivers of chronically ill patients: Prevalence, quality of life (QOL) and association with psychological stress. DDW 2010; Abstract M1337

Full reports from Digestive Disease Week can be found on

References: 1. Colpermin SmPC. May 2008.McNeil Products Ltd. 2. White DA et al. Int J Pharm 1987; 40: 151-5.

a request-only electronic journal.

3. NICE Clinical Practice Guideline. Irritable bowel syndrome in adults: Diagnosis and management of irritable bowel syndrome in primary care. Feb 2008.

4. Ford AC et al. BMJ 2008; 337: a2313.

Please email:

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to McNeil Products Limited on 01344 864 042.

subscriptions@icr-uk.com and mark your email ʻGastroenterology.MEDʼ

Date of preparation: June 2010

05773

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European Society of Hypertension - by Peter Mas-Mollinedo Reports from the ESH scientific meeting, Oslo

Update on trial results revealed at ESH

B

lood pressure (BP) is an important determinant of kidney disease among patients with diabetes.

Previously the recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75mmHg for people with diabetes and nephropathy, respectively. The previously reported ONTARGET study showed that lower is not necessarily better when it comes to blood pressure in this patient population, with coronary heart disease or diabetes plus additional risk factors. Although there was evidence that lower was better in terms of stroke, there was a suggestion of harm when BP was reduced below 130mmHg systolic for the outcome of cardiovascular death in diabetics. Studies presented at the ESH in Oslo, added more evidence to this debate and a Canadian primary care study also showed the benefits of awareness in the community at reducing CV events.

RESULTS FROM THE ACCORD BP TRIAL

I

ntensive blood pressure (BP) control did not reduce the rate of a composite outcome of major cardiovascular (CV) events in high-risk patients with Type 2 diabetes mellitus (DM), according to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP Trial.

However, intensive BP control correlated with reductions in the rate of total stroke and nonfatal stroke. Richard H. Grimm, MD, PhD, Berman Center for Clinical Research, Minneapolis, MN, presented new findings from the ACCORD BP Trial. The ACCORD Trial included 4733 patients with stable Type 2 DM of more than three months (average duration ten years) who were considered to be at high risk for CVD (defined as clinical or subclinical disease or ≥2 CV risk factors, in addition to DM). Patients were randomised to receive either intensive therapy (n=2362) (initial 2-drug therapy of thiazide-type diuretic plus an ACEi, an ARB, or a β-blocker was recommended with drugs added or titrated to achieve a systolic BP of <120mmHg or standard therapy (n=2371).

The target systolic BP for the intensive therapy group was <120mmHg versus <140mmHg for the standard therapy group. The primary outcome was the first occurrence of a major CV event (defined as nonfatal MI, nonfatal stroke, or CV death). Secondary outcomes included an expanded macrovascular outcome (defined as a combination of the primary outcome plus

‘

The rate of serious adverse events, although infrequent, was significantly higher in those who were treated with intensive therapy.

’

revascularisation or hospitalisation for congestive heart failure), major coronary disease events (defined as a combination of a fatal coronary event, a nonfatal MI, or unstable angina), hospitalisation or death due to heart failure, all stroke, death from any cause, or death from CV causes.

The rate of serious adverse events, although infrequent, was significantly higher in those who were treated with intensive therapy compared with those who received standard therapy (3.3% vs. 1.3%, respectively; p<0.0001). One year from study end, the mean systolic BP averaged 119.3mmHg versus 133.5mmHg for intensive and standard groups, respectively, amounting to a difference of 14.2mmHg. The annual rate of the composite of fatal and nonfatal CV events was similar in both groups (1.87% vs. 2.09% per year for standard therapy; p=0.20). There was no difference in death from any cause between the two groups.

The pre-specified secondary outcomes of total stroke (p=0.01) and nonfatal stroke (p=0.03) were lower in the intensive therapy group. Based on these findings, the number needed to treat to lower systolic BP in order to prevent one stroke over five years would be 88.

Interactions were also observed related to stroke rates and age (interaction p=0.13), CVD history (interaction p=0.94), baseline haemoglobin A1c (interaction p=0.008), and baseline diastolic BP (interaction p=0.10).

The results failed to demonstrate that lower target systolic BP (<120mmHg), through the use of intensive therapy, reduces the rate of fatal and nonfatal CV events (composite primary endpoint) in high-risk patients with Type 2 DM. However, interesting data emerged regarding the secondary endpoints of total stroke and nonfatal stroke. These stroke related interactions merit further evaluation.

ROADMAP MICROALBUMINUREA

E

arly treatment with the angiotensin receptor blocker (ARB) olmesartan significantly reduced the risk of developing microalbuminuria among patients with Type 2 diabetes, according to new interim findings from the ongoing Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) trial.

The ROADMAP trial was designed to evaluate whether early intervention with an CONTINUED ON PAGE 16 >

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European Society of Hypertension - by Peter Mas-Mollinedo Reports from the ESH scientific meeting, Oslo

Update on trial results revealed at ESH

< CONTINUED FROM PAGE 15

ARB prevented or delayed the onset of microalbuminuria, an early marker of renal disease and future CV events, in patients with Type 2 diabetes. The multicentre randomised trial included 4449 men and women with Type 2 diabetes, normal kidney function, and at least one additional CV risk factor, including hypertension. The mean baseline blood pressure (BP) level was 136/81mmHg. Participants were randomly assigned to treatment with olmesartan 40mg daily (n=2232) or placebo (n=2215). Patients were permitted to receive other antihypertensive medications during the study, but not other angiotensin-converting enzyme (ACE) inhibitors or ARBs. The primary endpoint was time to onset of microalbuminuria, and secondary endpoints included renal and cardiovascular events. Hermann Haller, MD, Hannover Medical School, Hanover, Germany, presented 48-month findings from the ongoing ROADMAP trial.

Treatment with olmesartan was associated with effective BP control. After 48 months, 78.2% and 71.3% of patients in the

olmesartan and placebo groups, respectively, reached target BP levels of <130/81mmHg. Patients in the olmesartan group were 23% less likely than those in the placebo group to develop microalbuminuria at 48 months (HR, 0.770; p=0.0104). The reno-protective benefit of olmesartan was independent of its effect on BP. Microalbuminuria was less common in the

‘

Patients in the olmesartan group were 23% less likely than those in the placebo group to develop microalbuminuria at 48 months.

’

olmesartan group after correcting for differences in diastolic BP (HR, 0.810; p=0.0398) and systolic BP (HR, 0.814; p=0.0451) between the ARB and placebo groups.

According to a safety analysis, olmesartan showed no detrimental effects on renal outcomes at 48 months. The composite risk of

CV morbidity and mortality was 4.3% in the olmesartan group and 4.2% in the placebo group (HR, 1.00; p=0.99). Fatal CV events were rare, but occurred more frequently in the olmesartan group (n=15) than in the placebo group (n=3; HR, 4.94; p=0.01). The risk of CV mortality with olmesartan relative to placebo was significantly increased only among patients with pre-existing CVD (p=0.02). CV deaths in the olmesartan group were also associated with hypotension, occurring more frequently in patients with the lowest systolic BP levels and in those who experienced the greatest reduction in systolic BP. During discussions questions were raised as to whether a population who is hypotensive with pre-existing CV disease should receive a potent hypertensive agent, as this would not normally happen in clinical practice. Discussion also centered around the ‘J’ shaped curve phenomenon and reducing BP beyond 130/80mmHg and the ROADMAP study adds to this evidence.

In June, the U.S. Food & Drug Association (FDA) announced that it is reviewing interim safety data from ROADMAP and the Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT), which also showed excess CV mortality with olmesartan compared with placebo. According to Professor Haller, an observational follow-up study of ROADMAP is underway to further understand the long-term benefits of preventing the onset of microalbuminuria in patients with Type 2 diabetes.

CASE-J STUDY EXTENSION is a FREE request only e-journal for healthcare professionals delivered to you by email The editorial will be drawn from key international conferences such as the European Society of Cardiology and British Hypertension Society annual meetings as well as major journals and symposia.

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Journal and Literature Reviews

Local and International News

Case Studies

Conference Reviews

Web Links

E V I D E N T I A • V O L U M E 4 • I S S U E 4 • J U LY / AU G U S T 2 0 1 0

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three-year extension of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Study demonstrated comparable efficacy of the angiotensin receptor blocker candesartan and the calcium channel blocker amlodipine on the incidence of cardiovascular (CV) events in high-risk hypertensive Japanese patients.

Candesartan exhibited sustained superiority over amlodipine with regards to reduction in new-onset diabetes throughout the 3-year extended follow up.

Kazuwa Nakao, MD, Kyoto University,

Kyoto, Japan, presented findings from the CASE-J extended follow-up study.

The Case-J Extension included 2,232 hypertensive patients from the original trial who were randomised to either candesartan (n=1140) or amlodipine (n=1092). The two groups at baseline had a mean SBP of 163mmHg and a mean DBP of 92mmHg. The mean age of study participants was 64 years and the mean BMI was 24.5. The two groups also had similar co-morbidities and risk factors at baseline. The primary composite endpoint was the incidence of CV mortality and morbidity, defined as sudden death and CV, cardiac, renal, and vascular events. The secondary endpoints included the incidence of all-cause death, CV death, and new-onset diabetes.

BP was well-controlled in both treatment groups throughout the duration of the early trial and this benefit was maintained over the extended course of follow-up. There was no significant difference in the incidence of CV events between the two groups. Analysis of single primary endpoint components (sudden death, CV events, cardiac events, renal events, and vascular events) found no significant difference between candesartan and amlodipine treatment. The incidence of allcause death was also comparable for both treatment groups.

The results showed treatment with candesartan significantly reduced the incidence of new-onset diabetes compared with amlodipine during the original study arm (p=0.031) and this benefit was demonstrated further in the extension arm of the study. A 29% relative risk reduction of new-onset diabetes was observed in the candesartan group compared with amlodipine (HR, 0.71; 95% CI, 0.51 to 1.00; p=0.0495). There also appeared to be an interaction between BMI and new-onset diabetes (interaction p=0.187). Increases in risk reduction correlated with increased BMI, particularly in patients with BMI ≥27.5 (p=0.049).

Findings from the CASE-J Extension study provide long-term data regarding the efficacy of candesartan and amlodipine on the incidence of CV events and new-onset diabetes in high-risk hypertensive patients.

While results were comparable for both treatments concerning CV events, the incidence of new-onset diabetes was

significantly reduced with candesartan compared with amlodipine and this benefit was sustained over time.

HEALTH AWARENESS CAN REDUCE EVENTS

A

1265 sessions took place (~25% of older adults attended at least one session). Pre- and post-CHAP data were documented and analysed (defined as 01/09/2005-31/08/2006 and 01/09/2007-31/08/2008, respectively).

The primary composite end-point was the rate of hospital admissions for acute myocardial infarction (AMI), congestive heart failure (CHF), and stroke among community residents aged ≥65 years. A significant decrease in hospital admissions for the composite endpoint was observed in the CHAP group compared with control (RR, 0.91; 95% CI, 0.86 to 0.97; p<0.01). The CHAP communities demonstrated a 6% decrease in hospital admissions during the aforementioned time period, while the control communities demonstrated a 3% increase. The rate of hospital admissions for AMI and CHF also favored the CHAP approach compared with control (p<0.01 for AMI and p=0.03 for CHF).

CHAP resulted in lower rates of in-hospital death (p=0.06) and fewer instances of hypertension therapy initiation (p=0.02).

This innovative approach to CV risk reduction resulted in significant decreases in CV morbidity. It appeared to be wellreceived, as there was a high rate of participation on the part of the health professionals, the peer volunteers, and the community participants. The CHAP study demonstrated that this is an effective approach to CV management and risk reduction at the community level. More information regarding this program can be found at www.CHAPprogram.ca

community outreach programme aimed at improving cardiovascular (CV) health awareness is an effective, feasible approach to CV management and risk reduction, according to results from the Community Cardiovascular Health Awareness Program (C-CHAP). Lisa Dolovich, a Pharmacist at McMaster University, Hamilton, Ontario, Canada, presented results from this Canadian community cluster, randomised, controlled.

C-CHAP was designed to evaluate the effectiveness of a CV health awareness programme in reducing the incidence of stroke and CV morbidity at the community level (population 10,000 to 60,000). Randomisation included 39 communities with participating family physicians and pharmacists, of which 20 received intervention. C-CHAP intervention consisted of community-wide CHAP session promotion, trained peer volunteers who monitored blood pressure (BP) measurements (via an automated device) and administered standardised CVD and stroke risk assessments, and local educational resources targeting specific modifiable risk factors provided to all participants. BP and risk assessment data were entered into a centralised, web-based data management system and was disclosed to clinicians and participants. Community health nurses and pharmacists were made available to those participants who had high BP readings and follow-up was arranged for those participants who were deemed high-risk.

CHAP education sessions were held on a weekly basis for all participants.

In the autumn of 2006, CHAP was successfully launched in 20 randomly selected communities with 214 active physician participants and 129 active pharmacy participants. Assessments Trained peer volunteers monitor blood pressure (BP) were performed on 15,889 measurements (via an automated device) and administer unique participants and standardised CVD and stroke risk assessments E V I D E N T I A • V O L U M E 4 • I S S U E 4 • J U LY / AU G U S T 2 0 1 0

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

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

candesartan cilexetil

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

Prescribing Information – Amias® (candesartan cilexetil) (Refer to Summary of Product Characteristics before prescribing) Amias® (candesartan cilexetil) Abbreviated Prescribing Information Presentation: Tablets containing 4mg, 8mg, 16mg or 32mg candesartan cilexetil. For specific patient populations 2mg.

Indication: Essential Hypertension; Treatment of patients with heart failure and left ventricle systolic dysfunction (LVEF ≤ 40%) as add-on therapy to ACE-inhibitors or when ACE-inhibitors are not tolerated.

Dosage: In hypertension: Starting and usual maintenance dose is 8mg od with or without food. If necessary, the dose can be increased to 16mg od. If after 4 weeks blood pressure is not sufficiently controlled, the dose may be increased further to 32mg od. No dose adjustment is necessary in the elderly. A starting dose of 4mg is recommended for patients with renal impairment (including haemodialysis) and those at risk of hypotension due to intravascular volume depletion.

For patients with mild to moderate hepatic impairment, the recommended starting dose is 2mg. In heart failure: Usual starting dose is 4mg od with or without food. Up-titration to the target dose of 32mg od or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks. No dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion, renal impairment or mild to moderate hepatic impairment. Amias can be administered with other heart failure treatment including ACEinhibitors, beta-blockers, diuretics and digitalis or a combination of these. Safety and efficacy of Amias not established in children.

Contra-indications: Hypersensitivity to any component of Amias.

Pregnancy and lactation. Severe hepatic impairment and/or cholestasis. Warnings and Precautions: Monitoring of serum potassium and creatinine levels is recommended during dose titration of Amias in patients with heart failure and regularly in patients taking concomitant ACE-inhibitors and potassium sparing diuretics such as spironolactone. Periodic assessments of renal function is also recommended especially in elderly heart failure patients ≥ 75 years and in heart failure patients with impaired renal function. Hypotension may occur during treatment with Amias in heart failure patients. Risk of increased blood urea and serum creatinine in patients with renal artery stenosis. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment.

Amias should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted. Possible hypotension during anaesthesia and surgery. Not recommended in patients with primary hyperaldosteronism. As with other vasodilators, use with caution in patients with aortic and/or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Drug Interactions: No clinically significant interactions identified.

Possible interaction with NSAIDs. Anti-hypertensive effect of Amias may be enhanced by other antihypertensives. Careful monitoring of serum lithium levels recommended during concomitant use. Increase in serum potassium may occur with potassium supplements and potassium sparing diuretics. Side-effects: In hypertension clinical trials,

adverse events were mild and transient with the overall incidence comparable to placebo. Overall incidence showed no association with dose or age. Adverse events in clinical trials include: headache, respiratory infection, back pain and dizziness/vertigo. In heart failure clinical trials (e.g. CHARM), the adverse event profile of Amias was consistent with the pharmacology of the drug and health status of the patients. In the CHARM clinical programme, 21% of the Amias group and 16.1% of the placebo group discontinued treatment due to adverse events. Adverse reactions commonly seen were: hypotension, hyperkalaemia, renal impairment and increases in creatinine, urea and potassium. Postmarketing there have been very rare reports of: nausea, increased liver enzymes, abnormal hepatic function or hepatitis, arthralgia, myalgia, back pain, angioedema, rash, urticaria, pruritus, dizziness, headache, leucopenia, neutropenia, agranulocytosis, hyperkalaemia, hyponatraemia, decreased haemoglobin, increased creatinine and urea, and renal impairment/failure.

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

Adverse events should be reported.

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

Legal Category: POM. Packs and Basic NHS Price: Blister packs. Amias 2mg, £3.39 for 7 tablets (PL 16189/0001); Amias 4mg, £3.68 for 7 tablets and £9.25 for 28 tablets (PL 16189/0002); Amias 8mg, £9.89 for 28 tablets (PL 16189/0003); Amias 16mg, £12.72 for 28 tablets (PL 16189/0004); Amias 32mg, £16.13 for 28 tablets (PL 16189/0007). PI Date Code: 01/2010 PI Approval Code: TA091232 Marketing Authorisation Holder: Takeda UK Ltd., Takeda House, Mercury Park, Wycombe Lane, Wooburn Green, High Wycombe, BUCKS HP10 0HH. For further information contact the Marketing Authorisation Holder: Telephone: 01628 537900, Fax: 01628 526615. ®Registered trademark owned by Takeda Pharmaceutical Company Ltd. References: 1. Lacourcière Y et al. Am J Hypertens 1999; 12: 11811187. 2. Gradman AH et al. Heart Dis 1999; 1(2): 52-7. 3. Bakris G et al. J Clin Hypertens 2001; 3: 16-21. 4. Vidt DG et al. J Hum Hypertens 2001; 15: 475-480. 5. Andersson OK and Neldam S. J Hum Hypertens 1997; 11(Suppl 2): S63-S64. 6. Young JB et al.

Circulation 2004; 110: 2618-2626.

Code: TA090661j Date of preparation: March 2010

Smoking Cessation report

Smoking cessation treatments work and are safe for people with severe mental illness

I

adverse effects. In general, people with SMI responded well to pharmaceutical and behavioural treatments, which doubled their chance of quitting.

Because most of the studies focused on people with well controlled psychiatric conditions, it was not possible to state how well people with acute mental illness (such as those who have experienced recent hospitalisation) would respond to smoking cessation treatment.

Professor Simon Gilbody from the University of York & Hull York Medical School, who co-authored the review, commented that "schizophrenia is a devastating condition which causes people to die 25 years earlier than the rest of the population. This is a huge health inequality, and it is largely due to smoking-related illness rather than schizophrenia itself."

Dr. Lindsay Banham, who led the People with severe mental illnesses (SMI) such as review, added "what this review schizophrenia have some of the worst physical suggests is that quit-smoking health of any section of the population treatments like nicotine replacement therapy may work just as well for people with those with SMI has largely been ignored and disorders like schizophrenia. Smoking by people with schizophrenia are not consistently offered treatment or services. We found evidence that smoking cessation treatments are effective and safe. We hope our research leads to better services for this neglected population."

Professor Gilbody concluded, "Despite huge expansion in smoking cessation is a FREE request only e-journal for healthcare services in recent years, people with severe professionals delivered to you by email mental illness have been left behind. The challenges for health services are to ensure The editorial will be drawn from key international conferences such as the people with schizophrenia are offered these European Academy of Allergology & Clinical Immunology and European treatments, and that services reflect the Respiratory Society annual meetings as well as major journals and symposia. needs of this population.''

n a study published in the journal Addiction, researchers have determined that treatment for smoking dependence is as effective among people with severe mental illnesses as it is for the general population. Importantly, they also found that offering such treatments does not appear to cause deterioration in mental health.

This is good news: people with severe mental illnesses (SMI) such as schizophrenia have some of the worst physical health of any section of the population. They are two to three times more likely to smoke, and smoking-related illnesses contribute significantly to their high sickness and death rates. Mortality rates for those with SMI are three times that of the rest of the population.

Although treatment for smoking dependence would improve the physical health of people with SMI, the medical community has traditionally ignored health promotion and worried that such treatments would worsen people's mental states.

The authors brought together the most rigorous evidence on smoking cessation treatment among people with SMI. They were able to determine the effectiveness of smoking cessation treatment and chart any predictable

Journal and Literature Reviews

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Reference: Banham L. and Gilbody S. Smoking cessation in severe mental illness: What works? Addiction 2010; 105: doi:10.1111/j.1360-0443.2010.02946

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Smoking Cessation report

Positive messages are better for tobacco cessation

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elling people about the benefits of quitting is more likely to help smokers break the habit, than scaring them with the dangers of continuing, researchers found. Callers to a tobacco quitline were nearly twice as likely to stop in the short term when they got positive messages rather than negative ones in a randomised trial led by Benjamin A. Toll, PhD, of Yale University School of Medicine. The effect lasted less than three months, Toll's group reported online in the Journal of the National Cancer Institute.

Still, that's a good start, although one or two years is the ultimate test of cessation, said Thomas J. Glynn, PhD, of the American Cancer Society.

Telephone-based counselling The notion that positive messages are more motivating shouldn't be a surprise, considering findings from other branches of medicine, Glynn said. Furthermore, the very fact that people call the quitline suggests that they are already aware of the risks of smoking and may not need them reiterated, he said. His organisation and agencies in all 50 states have some type of free, telephone-based counselling programme to help smokers quit, but the call centres typically employ a mix of positive and negative messages - determined by the individual counsellor, Glynn noted. These results suggest that "going right into positive mode may be best," he said, a strategy that physicians should also consider adopting when faced with a patient who's thinking about quitting. Quitlines reach only about 1% of the nation's smokers, but the technology is fairly new, Glynn said: "They've really only come into their own in the last decade." Research has been far outpaced by rapidly evolving programmes, which now may include Internet and even text messaging components, added Robert T. Croyle, PhD, of the National Cancer Institute in Maryland.

In an accompanying editorial, Croyle cautioned that the study results were

20

weakened by confounding since the duration of the positive messages was longer. The trial included 28 counsellors working at the New York State Smokers' Quitline who were randomly assigned to provide standard or "gain-framed" counselling and print materials to the 2032 callers. All medically-eligible callers were mailed a two-week starter pack of a nicotine replacement system.

Effective training Standard messages included both a discussion of the costs of smoking and the benefits of quitting whereas the gain-framed version focused on positive effects of quitting.

For example, "If you quit smoking you will be more likely to resist colds and flu" was the gainframed variation of "Smokers are more likely to get colds and flu." The training for counsellors appeared effective, as those who were to provide gain-framed statements actually did so

‘

Callers to a tobacco quitline were nearly twice as likely to stop in the short term when they got positive messages rather than negative ones.

’

significantly more often than the control group counsellors (3.9 versus 1.4 mean messages on achieving benefits and 1.5 versus 1.0 mean gain-framed messages for avoiding negative consequences, both P<0.001). Callers appeared to benefit as well. When surveyed two weeks after their initial call, 23.3% who got the positive messages had been tobaccofree for the prior 24 hours compared with just 12.6% in the standard message group (odds ratio 2.1, P<0.001).

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limitations Quit attempts, whether successful or not, were more common as well at two weeks (31.1% versus 16.7%, P<0.001). However, the effect of positive messaging was short-lived. By the three-month follow-up, abstinence rates over the prior seven days was similar between groups (28.4% gain-framed versus 26.6% standard messages, P=0.48). Use of nicotine replacement therapy was likewise no different between groups at three months (P=0.25).

"Multiple messages may be necessary for longer-term impact," Toll's group wrote. The researchers noted that the results would need to be replicated by other quitlines.

They cautioned, too, that the gain-framed group got an extra 2.5 minutes with the counsellor (mean call length 14 minutes and 37 seconds versus 12 minutes and 8 seconds, P=0.001). Other limitations included the low intensity of the intervention due to the brief contact, low follow-up rates, and potentially limited generalisability.

Disclosure: The study was funded by grants from the National Institutes of Health, the National Cancer Institute, National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism; by a contract from the New York State Department of Health; and by the State of Connecticut Department of Mental Health and Addictions Services. One of the researchers reported receiving honoraria as a member of workgroup on medications development for alcoholism sponsored by the American College of Neuropsychopharmacology and travel reimbursement for talks at the Controlled Release Society, the Drug Information Association, and the Association for Medical Education and Research in Substance Abuse. She also reported consulting for the University of Chicago on studies of naltrexone (ReVia) for smoking cessation. Glynn reported sitting, unpaid, on an advisory board for Pfizer.

Croyle provided no information on conflicts of interest.

References: Toll BA, et al. "Randomised trial: Quitline specialist training in gain-framed vs standard-care messages for smoking cessation" J Natl Cancer Inst 2010; 102: 1 – 11.

Croyle RT "Increasing the effectiveness of tobacco quitlines" J Natl Cancer Inst 2010; 102: DOI: 10.1093/jnci/djp476

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

Continuous abstinence rate weeks 9-12 (%)

CHAMPIX can help your mild to moderate COPD patients stop smoking1

42.3%

40

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

30 20

8.8%

10 0

CHAMPIX 1 mg bd (n=248)

placebo (n=251)

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

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

Date of preparation: January 2010 CHA851b ©Pfizer 2009

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

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

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

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

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

American Psychiatric Association - by Peter Mas-Mollinedo Report from the APA annual meeting, New Orleans

Mental Illness linked to tobacco exposure in womb

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renatal exposure to tobacco smoke may increase the risk of psychiatric disorders later in life, a Finnish researcher said at the APA meeting in New Orleans. The finding comes from analysis of medical records of 175,869 people born in Finland from 1987 through 1989, according to Mikael Ekblad, a doctoral student at Turku University in Finland. Those whose mothers smoked had up to a 44% increased risk of using psychiatric drugs in adult life, Ekblad reported in a poster session at the Pediatric Academic Societies.

"They have an increased risk of psychiatric illness and therefore the need for psychiatric drugs," said Ekblad. The researchers used the Finnish Medical Birth Register to collect data on maternal smoking (no smoking, fewer than ten cigarettes a day, or more than 20), as well as other factors, including gestational age, maternal age, and Apgar score. About 15% of the mothers reported smoking during pregnancy. The researchers obtained data on the children's use of psychiatric drugs for the years 1994 through

2007 from the country's drug prescription register, which reimburses patients for part of the cost of any medication deemed medically necessary. The sample excluded children with major congenital anomalies, Ekblad said. The researcher found a significantly increased risk of

‘

• Those whose mothers smoked more than ten cigarettes a day had an adjusted odds ratio of 1.44 (95% CI 1.36 to 1.53).

• The same dose response pattern was seen for all classes of psychiatric drugs, and all odds ratios were significant.

Those whose mothers smoked, have an increased risk of psychiatric illness

’

and therefore the need for psychiatric drugs.

the use of psychiatric drugs for children exposed to tobacco in utero. Specifically, compared with those whose mothers did not smoke: • Those whose mothers smoked fewer than ten cigarettes a day had an odds ratio, adjusted for background factors, of 1.25 (95% CI .20 to 1.31).

All, told, Ekblad said, 12.3% of the young adults had used psychiatric drugs, and of those, 19.2% had been exposed to tobacco smoke in utero. The finding is not entirely new, according to Jonathan Winickoff, MD, of Massachusetts General Hospital in Boston, who was not involved with the study. Winickoff is chair of the tobacco consortium of the American Academy of Pediatrics. As far back as 1992, some studies had demonstrated such a link, he said. Also, it has long been known that maternal smoking can affect the placenta, often leading to low birth weight or prematurity. One strength of the current study, he said, is that the researchers excluded children with such congenital anomalies, which probably means that the increased risk is associated with the actual exposure to chemicals in tobacco smoke.

Disclosure: The study was supported by the South-West Finnish Fund of Neonatal Research, the Finnish Foundation for Alcohol Studies, and the Turku University Hospital Research Foundation. Ekblad said he had no financial disclosures. Winickoff had no disclosures.

Reference: Ekblad M, et al. "The effect of prenatal smoking exposure on adolescents' use of psychiatric drugs" PAS

Prenatal exposure to tobacco smoke may increase the risk of psychiatric disorders later in life

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2010; Abstract 4401.56

EMA Highlights - by Gary Finnegan

Emerging Uses of EMA-Approved Drugs OMBUDSMAN CRITICAL OF MEDICINES AGENCY

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he European Ombudsman has criticised the European Medicines Agency over its refusal to release documents to researchers and patients, despite the EMA’s pledge to improve transparency.

The Agency refused to grant Danish scientists access to clinical trial data on two antiobesity drugs saying the data was commercially sensitive. Researchers from the Nordic Cochrane Centre claim studies supporting certain medicines are biased would not stand up to independent scrutiny.

The Ombudsman, P. Nikiforos Diamandouros, has given the EMA until the end of August to release the files or come up with a more compelling reason to keep them confidential. He said he has inspected the documents in question and does not believe they contain information that would have commercial implications.

According to Diamandouros, the Agency is guilty of “maladministration” for repeatedly withholding the reports which the Cochrane group first requested in 2007.

This is the second time this year that the Ombudsman has put the spotlight on the EMA. The Agency came under fire for refusing to allow an Irish citizen access reports linking an acne mediation with suicidal tendencies.

The EMA had claimed that EU transparency guidelines do not apply to adverse drug reactions but the Ombudsman saw things differently, saying medicines regulators’ work has a direct impact on public health and the widest possible access to documents should be given when requested.

EMA CHAIR REAPPOINTED

P

at O’Mahony has been re-elected as chair of the European Medicines Agency for a second three-year term.

Mr O’Mahony is Chief Executive of the Irish Medicines Board and pledged to ensure that the EU regulator continues to develop

for the good of the public.

The executive board of the EMA also agreed changes to how it handles potential conflicts of interest of experts involved in evaluating medicines. The new policy, which will formally be adopted in October, will mean scientists’ declarations of interests will be published in an effort to boost transparency.

Meanwhile, the European Commission is looking for three representatives from healthcare professional organisations and three members of patient groups to join the EMA paediatric committee (PDCO).

New members will be appointed for threeyear terms beginning in 2011. The Committee meets for three consecutive days each month in London to discuss medicines for children.

REGULATOR TEAMS UP WITH ADDICTION CENTRE

T

he EMA has signed a cooperation agreement with the European Monitoring Centre for Drugs and Drug Addiction, in a move designed to avoid duplication of their work.

The two agencies have several areas of overlap and common interest and have previously worked closely to exchange information and share expertise.

Cooperation in the area of new psychoactive substances and regular consultation on misuse of medicinal products is also central to the new arrangement which will see officials from both agencies meet regularly.

The two bodies have agreed to inform one another on matters of common interest but have signed strict confidentiality clauses to ensure data related to identifiable individuals is not misused.

NEW MEDICINES APPROVED

T

he Committee for Medicinal Products for Human Use (CHMP) has adopted positive opinions recommending the granting of marketing authorisations for the following new medicines:

Brinavess (vernakalant), from Merck Sharp & Dohme Ltd, intended for the rapid conversion of recent onset of atrial fibrillation to sinus rhythm in adults.

Rapiscan (regadenoson), from Gilead Sciences International Ltd, intended as pharmacological stress agent for radionuclide myocardial perfusion imaging.

Ruconest (conestat alfa), previously known as Rhucin, from Pharming Group N.V., an orphan medicine intended for the treatment of angioedema attacks. The active substance in Ruconest, conestat alfa, is produced using recombinant DNA technology. It is extracted from the milk of rabbits that have had a gene (DNA) inserted, which makes them able to produce the human protein in their milk. This was a resubmission of an application for a marketing authorisation following a negative opinion by the CHMP in December 2007.

Sycrest (asenapine), from N.V. Organon, intended for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults.

Vpriv (velaglucerase alfa), from Shire Pharmaceutical Ireland Ltd, an orphan medicine intended for the treatment of Gaucher disease.

The Committee carried out an accelerated assessment of this medicine, due to a major public health interest. In the light of the ongoing shortage of the authorised medicine for the treatment of Gaucher disease, the CHMP found that Vpriv might constitute an alternative treatment option for this condition.

Positive opinion for a ‘hybrid generic’ The Committee adopted a positive opinion recommending marketing authorisation for PecFent (fentanyl), from Archimedes Development Ltd, intended for the treatment of breakthrough pain in adults who are already receiving maintenance opioid therapy for chronic cancer pain. PecFent is a ‘hybrid generic’ medicine. This means that this medicine contains a known active substance, but is presented in a new pharmaceutical form (nasal spray). The medicines Actiq lozenges and Effentora buccal tablets are the reference products.

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American Society of Clinical Oncology - by Bruce Sylvester Reports from ASCO, Chicago

Highlights from ASCO Annual Meeting Approximately 30,000 clinicians, industry representatives and journalists attended the ASCO annual meeting in Chicago in June, 2010.

Highlights from the clinical trial presentations appear below, as reported by staff writer, Bruce Sylvester, who attended the meeting.

RITUXIMAB IN REDUCED RISK OF LYMPHOMA PROGRESSION

M

aintenance therapy with rituximab following induction with rituximab-pluschemotherapy significantly improves outcomes in follicular lymphoma, investigators reported at ASCO. “These findings offer new hope in the management of this disease. Rituximab maintenance should be considered as a standard of care in first-line follicular lymphoma,” said presenter and lead investigator Gilles Salles, MD, professor in the department of hematology at the Centre Hospitalier Lyon-Sud, Lyon, France.

In the PRIMA (Primary Rituximab and Maintanence) study, rituximab plus either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine, prednisone) or FCM (fludarabine, cyclophosphamide, mitoxantrone) chemotherapy was used as initial treatment.

Patients who responded (1018/1217) were randomised to receive either rituximab monotherapy maintenance (375mg/m2 i.v. every 2 months for 24 months, n=505) or to observation (n=513).

The primary endpoint was progression-free survival (PFS), and was it evaluated at the planned 24-month interim analysis. Median follow-up time was 25 months from randomisation and 31 months from study entry.

At the interim analysis, rituximab maintenance had significantly (p<.0001) reduced the risk of lymphoma progression by 50% (HR=0.50, 95% CI 0.39; 0.64). An independent response review committee confirmed the finding.

Also, rituximab maintenance decreased by 39% (HR=0.61, p<-0003) the risk of initiating a new anti-lymphoma treatment.

The most common adverse events were infections, 22% in the observation arm and 37% in the rituximab maintenance arm.

The authors concluded that two years of rituximab maintenance therapy after induction

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immunochemotherapy in previously untreated follicular lymphoma patients significantly improves progression-free survival with little additional toxicity.

The study was supported by Roche Pharma.

DAILY DASATINIB IN CP-CML

F

ollow-up data from 4 years indicates long-term efficacy of dasatinib 100mg/daily for treating chronicphase chronic myeloid leukemia (CP-CML).

“Dasatinib 100mg was the best tolerated dose, with few grade 3/4 side effects being reported between 24 and 48 months of followup,” lead investigator Neil Shah, MD, assistant professor, division of hematology/oncology at the University of California in San Francisco, said in his poster presentation at ASCO. The objective of the study was to evaluate four year efficacy and safety of dasatinib 100mg/daily in patients with CP-CML following imatinib resistance or intolerance, and to assess the predictive value of cytogenetic response at 6 and 12 months for dasatinib 100mg /daily on long-term progression-free survival (PFS).

The investigators randomised 662 subjects using a 2x2 factorial design to 1 of 4 treatment arms: 100mg once daily (n=167), 50mg twice daily (n=168), 140mg once daily (n=167), and 70mg twice daily (n=168).

The investigators reported that, at four-year follow-up, patients on dasatinib 100mg achieved 66% PFS and 82% overall survival (OS). They also achieved a 4% rate of transformation to accelerated phase/blast crisis (AP/BC ) at 48 months.

The researchers reported that response to dastinib 100mg/daily at 6 and 12 months was predictive for PFS at 48 months. Achievement of a complete cytogenetic response (CCyR) at six months associated with 93% PFS at 48 months compared with 67% for subjects with partial cytogenetic response (PCyR).

Achievement of CCyR (with or without MVR) at 12 months associated with an 87% PFS rate, and achievement of a PCyR associated with a

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79% PFS rate, compared with a PFS rate of 45% for subjects with other/no cytogenetic response.

PFS, OS and AP/BC transformation outcomes were similar for all drug doses at 48 months.

Dastinib 100mg/daily showed the lowest rate of patient withdrawals for drug toxicity (16% vs. 22% [140mg/daily], 19% [50mg/twicedaily] and 26% [70mg/twice-daily]) Dasatinib is currently under evaluation as first-line therapy in patients with CP-CML. The study was supported by Bristol-Myers Squib.

LENALIDOMIDE SLOWS MULTIPLE MYELOMA PROGRESSION

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aintenance therapy with lenalidomide slowed progression of multiple myeloma by 54% in patients who had previously received highdose chemotherapy and an autologous stem cell transplant, researchers reported at ASCO. "If these results are confirmed in the final analysis, then it will suggest that maintenance therapy with lenalidomide can improve quality of life in patients with myeloma and delay the need for relapse therapy," said presenter and lead investigator Michel Attal, PhD, professor of haematology at Purpan Hospital in Toulouse, France. Final reporting of data on progressionfree survival and overall survival are expected in December 2010.

From July 2006 to August 2008, the investigators randomised patients, under 65 years of age, with non-progressive disease after a first line autologous stem cell transplantation ( performed within the last six months) to receive a consolidation with lenalidomide (25mg/day, 21 days/month, for two months) followed by a maintenance with either lenalidomide (10 to 15mg/day, n=314) until relapse or to placebo (n=314). Patient’s characteristics of each group were similar.

In December 2009, with a median follow up of 24 months from randomisation, the researchers performed the first pre-planned interim analysis.

The investigators reported that lenalidomide

maintenance therapy significantly improved three-year progression-free survival, with 68% of patients in the lenalidomide group showing no disease progression, compared with 35% in the placebo group (HR=0.46, p<.000001) They reported that there was from lenalidomide maintenance whether or not a patient had achieved a complete response after autologous stem cell transplantation .

Two-year overall survival was similar, at 95% for both groups. And maintenance lenalidomide was well tolerated.

The study was undertaken and funded by the Intergroupe Francophone du Myelome.

ZOLEDRONIC ACID REDUCES RATE OF SKELETAL-RELATED EVENTS Zoledronic acid appeas to be superior to clodronate for the preventing skeletalrelated events in patients with newly diagnosed multiple myeloma, and it also improve survival through anti-cancer activity. Researchers reported these findings at ASCO. “These data further support the anticancer activity of zoledronic acid and provide evidence that zoledronic acid should be considered for early integration into treatment regimens in patients with newly diagnosed multiple myeloma,” said presenter and lead investigator Gareth Morgan, Ph.D, Head of the Haemato-Oncology Unit at the Royal Marsden Hospital in London, UK. As background to the study, Dr. Morgan cited several preclinical studies suggesting anticancer activity for biphosphonates, with the highest activity seen in zoledronic acid for several types of cancer, including multiple myeloma.

In this trial, the research team investigated the effects of zoledronic acid compared to clodronate, another biphosponate, on skeletalrelated events, progression-free survival, and overall survival in multiple myeloma patients.

The investigators randomised 1970 newly diagnosed multiple myeloma patients (stage I, II and III) to zoledronic acid (4mg every 21-28 days) or clodronate (1600mg/day) plus standard anti-myeloma chemotherapy.

Treatment continued, at a minimum, until disease progression. Primary endpoints were: Overall survival, progression-free survival (as time from randomisation to disease progression, ergo new osteolytic lesions after the first two months of treatment) or death.

Secondary endpoints were skeletal-related events and safety.

Patient characteristics were similar at randomisation across the treatment groups.

To date, there are 1960 evaluable subjects

(zoledronic acid, n=981, median follow-up of 3.7 years and clodronate, n=979, median follow-up of 3.8 years).

The investigators reported that approximately 75% of the subjects have remained on zoledronic acid or clodronate treatment until their disease progressed.

The median time on treatment among discontinued patients was 156 days for clodronate and 270 days for zoledronic acid.

Also zoledronic acid therapy was associated with a reduction in the proportion of patients with a skeletal-related event, compared to clodronate (27.0% vs 35.3%, respectively; P = 0.0004).

Zoledronic acid subjects achieved 5.5 more months of overall survival time compared to clodronate subjects (50 vs 44.5 months, respectively; P = 0.0118) and 2 months greater progression-free survival (19.5 vs 17.5 months, respectively; P = 0.0179).

Dr. Morgan emphasised that the survival benefit for zoledronic acid was distinct from the prevention of skeletal-related events, suggesting that zoledronic acid might improve survival through anticancer activity.

Both treatments were generally well-tolerated.

The incidence of confirmed osteonecrosis of the jaw was low in real terms, but it was higher among zoledronic acid subjects compared to clodronate subjects (3.5% vs.0.3%).

The study was initiated and supported by the Medical Research Council Myeloma IX Study Group.

PHASED IPI AND P/C SHOWS PROMISE IN NSCLC

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authors noted that IPI is a fully human monoclonal antibody that inhibits CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4). This trial was a randomised, double-blind phase II study of first-line IPI in recurrent/metastatic lung cancer in combination with P/C. The purpose of the study was to evaluate the safety efficacy of ipilimumab/ paclitaxel/c arboplatin by two different combination schedules, concurrent and phased. In the concurrent combination schedule, ipilimumab is present as tumor antigen is released. In the phased schedule, ipilimumab is started after the tumour antigen is released.

The investigators randomised 204 subjects with chemotherapy-naive, recurrent or stage IIIb/IV NSCLC to receive either IPI (10mg/kg IV every 3 weeks) + concurrent IV P/C (175mg/m2 and AUC (area under curve, mg/ml×min) =6, every 3weeks, n=70) or IPI + sequential/phased P/C (n=68) or placebo (n=66).

Baseline patient characteristics were similar between the arms.

Following P/C chemotherapy, subjects received IPI as continuation maintenance therapy every 12 weeks until terminated due to toxicity or disease progression.

The primary endpoint of the study was a comparison of immune-related progressionfree survival (irPFS) in concurrent therapy to that seen in sequential therapy.

For the primary endpoint of immune-related progression-free survival (irPFS), the median number of months to progression for concurrent therapy was 5.52 months compared to 5.86 months for sequential/phased therapy. For progression-free survival (PFS), the median number of months to progression for concurrent therapy was 4.11 months compared to 5.13 months for sequential/phased therapy.

There were no unexpected safety signals in any arms of the study.

“These results support further investigation of ipilimumab in NSCLC,” the authors concluded.

atients treated with investigative ipilimumab (IPI) inductionmaintenance therapy and paclitaxel/carboplatin (P/C) in a phased manner achieved an extended immunerelated progression-free survival in nonsmall cell lung cancer (NSCLC), when compared to P/C alone. Researchers reported this finding at ASCO. Full reports from the American Society of Clinical “In combination with paclitaxel/ carboplatin, Oncology annual meeting can be found in the phased schedule appeared superior to the concurrent schedule,” Thomas Lynch, MD, Director of Yale Cancer Center in a request-only electronic journal.

New Haven, Connecticut, said in his Please email: subscriptions@icr-uk.com poster presentation. and mark your email ʻOncology.MEDʼ As background, the

Oncology.med

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European Neurological Society - by Bruce Sylvestor Reports from the ENS annual meeting, Berlin

Margarine, processed meats and other foods can increase the risk of multiple sclerosis

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ncreased production of certain types of industrially produced foods - specifically of margarine, processed meat and sausage, jam and marmalade, chocolate and chocolate confectionary, sugar confectionary and beer - correlates statistically with an increased incidence of multiple sclerosis (MS). This conclusion from analysis of data from seven EU countries was presented by the German epidemiologist Dr. Klaus Lauer at the 20th Meeting of the European Neurological Society (ENS) in Berlin. ‘‘This data is not as yet evidence of a causal connection, but is a clear indication that such a connection may exist and thus should be closely investigated,’’ says Dr. Lauer.

In the course of a so-called ‘‘ecological study’’, the epidemiological analysis of data collected for major regions or population groups, data on industrial food production in seven EU countries were compared for possible MS correlation - with differing results.

A significantly higher incidence of MS was noted in countries with, per head of population, high production of these processed foods.

No statistical correlation was found between MS and the distribution of crude vegetable oils and fats, butter, cheese, condensed milk, canned vegetables, canned and bottled fruit, wheat flour, biscuits, beet sugar, cocoa powder, ice cream or for smoking and chewing tobacco, and snuff.

A lower incidence of MS was in fact observed in other countries with high production of canned fish and macaroni, spaghetti and similar products.

More thorough investigation urgently required ‘‘Since ecological studies don't investigate the individual but large groups, a direct causal relation cannot be deduced from them,’’ says Dr. Lauer. ‘‘That requires more extensive studies of the individual to investigate whether those who later contract MS have in fact previously consumed more of a certain foodstuff than those who have remained healthy. But an epidemiological correlation, such as we have

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now detected, is in any case a serious indication of such a possibility, and it is imperative that it be followed up by thorough investigation.’’

Source: ENS Abstract P615 Industrial food production in countries of the European Union and the prevalence of multiple sclerosis: an ecological analysis

DEPRESSION INTENSIFIES PAIN

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epression alters the processing of pain impulses as well as the sensitivity to pain. New evidence of this relationship was presented by Italian experts at the ENS. The anatomical cause of this connection may be due to the fact that, in part, the same regions and the same neurotransmitters responsible for the processing of emotional moods in the brain are also responsible for the processing of pain. This in turn could point the way to new therapies with which pain and depression could be treated simultaneously.

A group of Italian researchers directed from Prof. Michele Tinazzi, compared the pain threshold as well as the pain tolerance of 25 patients - all with newly diagnosed and still untreated deep depression - with the a healthy control group. 80% of the patients reported muscle, joint or headaches occurring at the same time as or after the onset of depression.

In the course of the study, both patients and the control group were subjected to standardised electrical pain impulses on both hands and feet. The results showed that in all body areas measured, pain threshold as well as pain tolerance were considerably lower among all patients with depression than among those in the control group. Those with depression were significantly more sensitive to pain, in other words.

Brain regions used in common therapy approach “Our study shows impressively that the purely physiological aspect of the pain threshold and the cognitive-emotional aspect

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of pain tolerance, i.e. how bearable or unbearable the pain seems to me, go hand in hand”, said Dr. Sandro Zambito Marsala (San Martino Hospital, Belluno, Italy). “The most likely reason is that processing of pain and emotion share specific regions of the brain just as they share specific neurophysiological signal transmission pathways.” Because the latter are substantially steered by serotonin and noradrenalin circuits, it stands to reason that serotonin-noradrenalin reuptake inhibitors simultaneously combat depression and pain and could therewith substantially simplify the therapy. “This hypothesis has to be verified first, however, through additional detailed studies”, cautions Dr. Zambito Masala.

Source: ENS Abstract P308 Pain threshold and tolerance in major depression disorder

NEW STUDY CONNECTS BODY WEIGHT TO HIGHER ALZHEIMER RISK

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orpulence is unhealthy, but under certain circumstances a few extra pounds can prove advantageous.

People with a lower body mass index (BMI) face a greater risk of common age-related dementia progressing into Alzheimer’s Disease or other forms of profound dementia. The findings are a result of a Milan University study in collaboration with the Karolinska Institute of Stockholm presented at the ENS 2010.

Researchers examined a total of 245 patients averaging 74 years old who had been suffering from mild cognitive impairment for approximately two-and-a-half years. The mental capabilities of about half the patients remained stable during that period. About two thirds of those whose condition had deteriorated developed Alzheimer’s Disease.

The remaining third developed another form of dementia. Those whose cognitive disturbance deteriorated had a significantly lower BMI (mean value of 23.81) than those whose condition had remained unchanged (BMI mean of 25.47). Especially significant was the

Multiple sclerosis, migraine and dementia: new insights from neuroimaging Imaging techniques such as functional MRI or diffusion tensor imaging permit a direct and accurate look into the human brain. They allow observation of events from cellular changes to processes activated when people act, think and feel. Thus neurological diseases such as MS, dementia and migraine can be better predicted, diagnosed and treated.

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“ nnovative imaging techniques such as functional MRI or diffusion tensor imaging occupy an important place in modern neurology today. With their help we can better understand diseases such as multiple sclerosis, dementia, amyotrophic lateral sclerosis or Alzheimer's disease,“ says Prof. Massimo Filippi (Milan), committee member of the Annual Meeting of the European Neurological Society (ENS).

The proven imaging techniques in neurology, also referred to as neuroimaging, include technologies such as functional magnetic resonance imaging (fMRI), diffusion tensor imaging or voxel based morphometry (VBM).

These technologies provide precise images of the structure of the brain and allow doctors to observe the functional processes in the human

elevated risk of deterioration among those patients with a BMI of 23 or under.

brain, from cellular changes to processes activated when people act, think and feel. “We have to learn to understand the central nervous system. That is the only way we can gain insights into the development of diseases and improve treatments,“ says Prof. Filippi.

Changes in white matter in the brain presage dementia Neurologists await with interest the results of numerous neuroimaging studies presented at the ENS congress. “We have gained interesting insights particularly in the area of early detection and diagnosis of dementia, multiple sclerosis, Parkinson's, ALS and migraine,“ says Prof.

Filippi. As an example he mentions diagnosis of dementia at an early stage, a pattern of disease found also in patients with Alzheimer's, and which affects around 35 million people worldwide. “We have discovered that the development of dementia in older people can be more precisely predicted on the basis of changes in white matter in the brain.“

Correlation still unexplained “The conclusion that corpulence can suddenly be recommended is false, of course,” warns Dr. Francesca Clerici, principal author of the study (Luigi Sacco University Hospital, Milan). “First of all, the elevated cardiovascular risk among overweight people remains an unaltered fact. And secondly, our observational study shows a statistical but as yet no causal connection. Additional studies will be needed to demonstrate whether or not body composition is a cause of dementia’s progression or, conversely, that progressive dementia is a cause of weight loss - perhaps due to a patient’s losing his or her appetite.”

Source: ENS Abstract: P504 Low body mass index predicts progression of MCI to dementia and Alzheimer’s disease

Better assessment of primary progressive multiple sclerosis up to five years “When we know how damage is accumulated in the brain, we can respond better to diseases and intervene more selectively,“ says Prof. Filippi. He and his research team presented a study investigating primary progressive multiple sclerosis (PPMS) at the ENS congress. PPMS presents one of the most severe courses of disease among MS, because the disease does not occur in phases, but instead the patient's condition constantly deteriorates. Using diffusion tensor imaging, researchers have examined the grey matter in the brain of MS patients. It could be demonstrated that the extent of tissue damage in the thalamus predicted the accumulation of MS related disability five years after.

MS patients with fatigue suffer greater grey matter atrophy In another study, scientists assessed ‘fatigue syndrome’, one of the most common symptoms of MS. These patients suffer continual exhaustion and thus significant loss of quality of life. Using a procedure known as voxel based morphometry (VBM), researchers were able to compare MS patients with and without fatigue and matched healthy volunteers. Significant differences were noted: MS patients with fatigue syndrome exhibited more severe grey matter atrophy in several frontal lobe areas of the left hemisphere, than the control groups.

Changes in the brain in migraine patients: a progressive disease?

Neuroimaging techniques don't always provide indicators for better diagnosis, early detection or improved etiopathology.

Sometimes the entire clinical picture has to be re-thought. Thus scientists now assume that migraine is a progressive disease. “We have been able to establish that the brain matter of migraine patients deteriorates with the duration of the disease,“ says Prof. Filippi. This assumption is based on a study comparing 82 migraine patients with different clinical characteristics. The results show that grey matter is affected in migraine patients according to the differing characteristics and duration of the disease.

Neuroimaging will continue in future to play an important role in research and treatment of neurological diseases. The goal is to improve techniques even further. Scientists are already focussing on a combination of functional MRI and EEG. They hope with this combination to gain new insights into how the human brain works.

Source: ENS Abstracts

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www.nejm.org

TWO SURGERIES SHOW SIMILAR EFFICACY FOR WOMEN WITH URINARY INCONTINENCE

T Reporting from some of the latest articles in

Journal Reviews by Bruce Sylvester

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wo surgical procedures that reduce symptoms of stress urinary incontinence, transvaginal sling (TVT) and transobturator midurethral sling (TOT), show similar efficacy in women for up to a year after surgery.

The study was published recently by the New England Journal of Medicine.

"Both procedures are done using minimally invasive techniques, but until now there haven't been any large prospective head-to-head randomised trials comparing the two popular techniques," said Gary Lemack, MD, University of Texas Southwestern Medical Center.

The authors noted that there have been questions about which sling is more effective and which has greater risk of complications. "At one year, the two groups of patients were assessed both objectively and subjectively about the success of their procedures," said Dr. Lemack.

"The outcomes appear very similar at one year regardless of the severity of the patient's stress incontinence symptoms."

Efficacy measures included urine leakage with straining or coughing during an exam with a full bladder. All subjects also wore a pad for 24 hours to see if there was leakage. Subjects kept a three-day diary and recorded any symptoms of stress incontinence. And they reported the need for any further treatments.

"The rates of success using objective measures in patients with the transvaginal sling were around 81% and 78% for patients who had the TOT procedure - equivalent by our preset criteria," Dr. Lemack said. "Rates of subjectively reported success were slightly higher in the transvaginal group and thus did not quite meet the criteria for equivalence."

One difference between procedures appears to be adverse events. The TVT showed a greater likelihood of intraoperative bladder injury and postoperative voiding dysfunction, and the TOT was associated with greater postoperative numbness and pain.

Dr. Lemack said physicians could use this new information to more advise candidates for surgery about the risks and benefits of either operation. He also suggested that more studies should be directed at determining whether any other parameters, such as bladder function, might be helpful in predicting treatment success.

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

AZITHROMYCIN CAUSES NO IMPROVEMENT IN CYSTIC FIBROSIS LUNG FUNCTION

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ystic fibrosis lung function does not improve for children and adolescents using azithromycin, compared to placebo, researchers reported in the recent issue of JAMA. "A vicious cycle of infection and inflammation causes progressive lung destruction and premature death in patients with cystic fibrosis (CF)," the authors wrote. "Treatment strategies have therefore included both antimicrobial and anti-inflammatory agents."

Clinical evidence had suggested previously that azithromycin benefits patients with CF. "Azithromycin is recommended as therapy for CF patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF," the authors said.

Lisa Saiman, MD, Columbia University, New York, New York, and colleagues conducted a randomised, placebo-controlled trial of children and adolescents with CF who were uninfected with P aeruginosa.

The endpoints were improved lung function and reduced pulmonary exacerbations. The trial took place at 40 CF care centres in the United States and Canada.

The investigators screened 324 CF patients, and 260 met study criteria. They were randomised to azithromycin therapy (n = 131) or placebo (n = 129). The average age of the participants was 10.7 years.

At 24 weeks, the researchers found that azithromycin treatment compared to placebo did not result in improved pulmonary function, as measured by the change in forced expiratory volume in one second (FEV1).

"However, analyses of exploratory end points demonstrated that when compared with the placebo group, the azithromycin group had a 50% reduction in pulmonary exacerbations, 27% reduction in the initiation of new oral antibiotics (other than azithromycin), some weight gain, and 0.34-unit increase in body mass index," the authors wrote. "There were no differences in treatment groups in the use of intravenous or inhaled antibiotics or hospitalisations."

They also reported that the azithromycin

subjects reported less cough and less productive cough, compared with placebo participants.

"Further studies of azithromycin are warranted to further investigate its potential use in this population," the authors concluded.

www.thelancet.com

ALLOPURINOL ENHANCES EXERCISE CAPACITY IN CHRONIC STABLE ANGINA

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llopurinol prolongs exercise capacity in chronic stable angina, offering a potential alternative treatment to more costly standard therapies. Researchers reported this finding in a recent issue of The Lancet.

As background, the authors noted that prior research suggested that allopurinol inhibits xanthine oxidase, which reduces energy required by the heart in each beat or 'stroke'.

Based on these findings, Allan D Struthers, MD, University of Dundee, United Kingdom, and colleagues evaluated whether high-dose allopurinol could prolong exercise capability in patients with chronic stable angina.

They enrolled 65 subjects (aged 18-85 years) with clinically diagnosed coronary artery disease, a positive exercise tolerance test and stable chronic angina pectoris (for at least two months) into a double-blind, randomised, placebo-controlled, crossover study.

They gave the subjects allopurinol 600mg per day or placebo for 6 weeks and then crossed all subjects over to placebo or allopurinol.

The primary endpoint was the time to ST depression, and the secondary endpoints were total exercise time and time to chest pain.

In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed.

Allopurinol increased the median time to ST depression to 298s (IQR 211-408) from a baseline of 232s (182-380), and placebo increased it to 249s (200-375; p=0.0002). The point estimate (absolute difference between allopurinol and placebo) was 43s (95% CI 31-58).

Allopurinol increased median total exercise time to 393 s (IQR 280-519) from a baseline of 301s (251-447), and placebo increased it to 307s (232-430; p=0·0003); the point estimate was 58s (95% CI 45-77).

Allopurinol increased the time to chest pain

from a baseline of 234 s (IQR 189-382) to 304s (222-421), and placebo increased it to 272s (200-380; p=0·001); the point estimate was 38s (95% CI 17-55). No adverse effects of treatment were reported.

"Allopurinol is inexpensive compared with some other antianginal drugs such as ranolazine and ivabradine, and has a favourable long-term (>40 years) safety record for the treatment of gout," the authors wrote. "Compared with older antianginal drugs (nitrates, beta blockers), allopurinol is better tolerated because it does not reduce blood pressure or heart rate, and does not cause many side-effects, such as headaches and tiredness, that occur frequently with nitrates and beta blockers."

"High-dose allopurinol significantly prolonged the time to ST depression, the total exercise time, and the time to angina in patients with chronic stable angina during a standard exercise test, suggesting that endogenous xanthine oxidase activity contributes somehow to exercise-induced myocardial ischaemia," they continued. "These results also show that highdose allopurinol prolongs exercise in stable angina pectoris…on the basis of our results, allopurinol is a useful anti-ischaemic treatment option in patients with angina that has the advantage of being inexpensive, well tolerated and safe in the long term. The precise place of allopurinol in the management of angina pectoris now needs to be explored further, but this drug might be especially appealing for use in developing countries where coronary artery disease is rapidly increasing in frequency and where access to expensive drugs or invasive treatments (angioplasty and bypass surgery) is often restricted."

BMJ British Medical Journal www.bmj.org

JUDGING HOSPITAL PERFORMANCE BY DEATH RATE IS A BAD IDEA, EXPERTS SAY

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ortality rates do not offer a good measure of the quality of hospital care and they should not be used to launch public inquiries, such as the investigation at the Mid Staffordshire (UK) hospital, experts said in the recent issue of the BMJ. The hospital standardised mortality ratio used in the United Kingdom and around the

world identifies hospitals where more patients die than would be expected, i.e. 'bad' hospitals, as well as hospitals with fewer deaths than expected, i.e. 'good' hospitals.

But, the experts note, the ratio might not be valid since it may not adjust well for the type of patients treated at a particular hospital or take into account measurement errors between hospitals.

Richard Lilford from the University of Birmingham and Peter Pronovost from Johns Hopkins University School of Medicine, say that "hospital mortality rates are a poor diagnostic test for quality" and "they should not be used to calculate excess deaths resulting from poor care." They noted that Mid Staffordshire hospital "was blamed for 400 excess deaths on this precarious basis." They wrote that, "the practice is kept alive by well-meaning decision makers who want the idea that mortality reflects quality to be true."

While agreeing that an argument can be made for using hospital mortality rates as an initial signal for further scientific study of the issue. But they warn that public inquiries based on the rates can lead to hospitals being unfairly singled out, possibly undermining improvements in other areas of hospital care.

Emphasising that health care providers should not be exempt from accountability or that patients should not be protected, they said, "the search for robust measurements should not be impeded by fixing prematurely on a parameter that offers false hope."

They suggest measuring quality by observing selected outcomes that more closely reflect quality of care. Notably, they advocate more use of direct measures of the quality of care by checking hospital case notes, as recommended by the (UK) House of Commons Select Committee.

"Examining selected case notes to ensure that the correct treatment has been given and errors avoided is much more informative than trying to pick out 'bad apples' using the blunt instrument of hospital wide mortality rates," they said.

"If we really want to improve care, then managers are going to have to learn more statistics and statisticians more management. In the meantime, performance management of medical care by hospital mortality is not the answer," they concluded.

In an accompanying editorial, Professor Nick Black at the London School of Hygiene & Tropical Medicine wrote that a shift to the approach advocated by the authors, "would gain the credibility and support of clinicians and provide a much richer and more valid account for the public of how a hospital was performing."

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Medical news from around the world - by Gary Finnegan

World Health Matters

UNITED STATES HIGH BMI LINKED TO ‘CONVENIENCE STORES’ Researchers at the University at Buffalo in New York have found that women with homes closer to a supermarket, relative to ‘convenience stores’, have lower body mass indexes (BMIs). They have also revealed that women’s BMI increases in areas with higher concentrations of restaurants.

The research, led by Dr. Samina Raja, professor of urban and regional planning, was published in the Journal of Planning Education and Research.

“In particular, three findings are significant,” says Dr Raja. “First, a greater number of restaurants within a five-minute walk of a subject's house was associated with a greater BMI, holding other factors constant.”

“Second,” she says, “on average, women who live within relative proximity to supermarkets and grocery stores - as opposed to convenience stores - tend to have lower BMIs.” “Third, and perhaps most important, the interaction of the food environment and the built environment in a neighbourhood carries significant consequences for obesity. For example, a diverse land-use mix, while

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beneficial for promoting physical activity, is tied to a net increase in BMI when that land is dominated by restaurants,” Dr. Raja says.

The researchers say future work on the built environment and health must take account of the role of the “food environment” in women’s health.

The latest figures from the US suggest that one third of adults are obese, with the prevalence slightly greater among women.

“The prevalence of obesity is a significant public health concern because it places individuals at risk for a variety of diseases, and the role of environmental factors in contributing to obesity has received a lot of attention. We have attempted here to explain the paradox of high BMI rates among women living in highly walkable inner city neighbourhoods,” Raja says.

The study has several limitations however, among them, the fact that the researchers did not know where their subjects shopped for food, only what outlets were closest geographically.

They also were not able to classify restaurants based on their quality - fast-food and sit-down restaurants were treated as a single category, even though they know that quality varies widely across different types of restaurants.

Nonetheless, the study is seen as offering some insight into how planning, regulation and incentives can be used to improve healthy eating habits.

Reference: Journal of Planning Education and Research, June 2010; vol. 29, 4: pp. 444-460

FINLAND CHEESE IMPROVES IMMUNE RESPONSE Scientists in Finland have discovered that cheese can help preserve and enhance the immune system of the elderly by acting as a

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carrier for probiotic bacteria. The research, published in FEMS Immunology & Medical Microbiology, reveals that daily consumption of probiotic cheese helps to tackle age-related changes in the immune system.

"The increase in the proportion of aged individuals in modern society makes finding innovative ways to thwart the deterioration of the immune system a priority," said lead author Dr. Fandi Ibrahim from the University of Turku in Finland. "The intake of probiotic bacteria has been reported to enhance the immune response through other products and now we have discovered that cheese can be a carrier of the same bacteria."

Dr. Ibrahim's team believes that the daily intake of probiotic cheese can tackle the agerelated deterioration of the immune system known as immunosenescene. This deterioration means the body is unable to kill tumour cells and reduces the immune response to vaccinations and infections. Infectious diseases, chronic inflammation disorders and cancer are hallmarks of immunosenescene.

To tackle immunosenescene the team targeted the gastrointestinal tract, which is the main entry for bacteria cells into the body through food and drink and is also the site where 70% of vital immunoglobulin cells are created.

The team asked volunteers aged between 72 and 103, all of which lived in the same care home, to eat one slice of either placebo or probiotic Gouda cheese with their breakfast for four weeks. Blood tests where then carried out to discover the effect of probiotic bacteria contained within the cheese on the immune system.

The results revealed a clear enhancement of natural and acquired immunity through the activation of NK blood cells and an increase in phagocytic activity.

"The aim of our study was to see if specific probiotic bacteria in cheese would have immuneenhancing effects on healthy older individuals in a nursing home setting," concluded Ibrahim. "We have demonstrated that the regular intake of probiotic cheese can help to boost the immune system and that including it in a regular diet may help to improve an elderly person's immune response to external challenges."

Reference: FEMS Immunol Med Microbiol. 2010 Jun 1; 59(1):53-9

ITALY LOW CALCIUM INTAKE LINKED WITH OSTEOPOROSIS Postmenopausal women who have a low calcium intake show a higher risk of developing both osteoporosis and hypertension, according to research presented at EULAR 2010, the Annual Congress of the European League Against Rheumatism in Rome, Italy.

In a study of 825 postmenopausal Italian women with hypertension, a significantly increased proportion of women (35.4%) who consumed a lower amount of calcium through intake from dairy sources, had a concurrent diagnosis of both hypertension and osteoporosis, compared with women who consumed a higher amount of calcium (19.3% p<0.001).

Further statistical analyses revealed that a lower calcium intake was associated with an increased risk of developing hypertension or osteoporosis over time when compared with controls. Women who consumed a lower amount of calcium were shown to be most likely to develop both conditions over time compared with women consuming a higher amount of calcium.

"Our study confirms that there may be a link between hypertension and low bone mass and that a low calcium intake could be a risk factor for the development of osteoporosis in postmenopausal women" said Professor Maria Manara, Department of Rheumatology, Gaetano Pini Institute, Milan, Italy, and lead author of the study. "Our work has also shown that a low calcium intake from dairy foods may be involved in this association and could be considered a risk factor for the development of hypertension and osteoporosis."

The 825 subjects involved in the study were recruited from a cohort of 9898 postmenopausal women referred to the osteometabolic unit of the Gaetano Pini Institute in Italy, from 2002.

Calcium intake from dairy sources was assessed by the number of standard servings of ~300mg calcium consumed by women in a week and subjects were stratified into 'quartiles' (lower 25%, median 50% and upper 25%). For each case, three controls were selected and matched for age. Women who had been treated with diuretics (drugs known

to affect the generation of new bone material) were excluded from the study.

Reference: Abstract number OP0055 at EULAR 2010, the Annual Congress of the European League Against Rheumatism, Rome, Italy

NETHERLANDS WIDE VARIATION IN BREAST CANCER TREATMENT A global study of how breast cancer patients are treated in Europe, Japan and Asia has revealed major differences in the use of drugs, surgery and radiotherapy.

The nine-country collaborative study, led by a Dutch researcher, compared the treatment of almost 10,000 women with international guidelines to see how closely doctors are following best practice.

According to results published in the British Journal of Surgery, only France and Belgium use radiotherapy in 100% of breast cancer cases despite international guidelines recommending that radiotherapy should be part of breast-conserving treatment.

In Japan and the US, 14% of patients did not receive radiotherapy, while 13% of patients in the UK and Ireland were not given radiation.

Data from the whole cohort shows 39% of women received radiotherapy after a mastectomy and 93% of women received radiotherapy after breast conservation treatment.

The research is based on data from 9779 women with an average age of 64 from 566 study sites in Belgium, France, Germany, Greece, Japan, the Netherlands, the UK/Ireland and the USA. "The primary aim of our five-year research study was to carry out an international randomised trial to evaluate the efficacy and safety of the breast cancer drug exemestane, alone or following tamoxifen" explains coauthor Professor CJH van de Velde from Leiden University Medical Center in The Netherlands.

"However, because we had recruited a large number of patients, we decided that this also provided us with an invaluable opportunity to examine how different

countries treat postmenopausal women with early breast cancer. The results of our study show wide international variations in the percentages of women who receive breast conserving surgery (BCS) rather than breast removal (mastectomy) and radiotherapy after surgery,” he said.

A total of 58% per cent of the women had T1 tumours (less than 2cm), 37% had T2 tumours (2-5cm) and 5% had larger/more advanced (T3/T4) tumours. Results showed 47% of the women had axillary nodepositive disease, where the cancer affects the lymph nodes.

The highest percentage of node-negative disease was observed in the countries with the highest percentage of T1 tumours – the USA, France and Germany.

In general, women with T1 tumours were more likely to receive BCS. However, despite the fact that T1 tumour rates were similar in the USA and France (74% and 76% respectively), 89% of T1 tumours were treated with BCS in France compared with only 55% in the USA. The study, known as the TEAM (Tamoxifen and Exemestane Adjuvant Multinational) trial, found that women with T2 tumours were more likely to receive a mastectomy than BCS, but this varied widely between countries, from 42% in France to 69% in the USA. The overall mastectomy rate for all tumours was 44%, with the lowest rate in France (19%) and the highest rate in Greece (56%). BCS was highest in women aged between 50 and 70 and mastectomy rates were highest in women under 50.

Some 82% of patients underwent Axillary Lymph Node Dissection, ranging from 75% in the USA to 99% in the UK and Ireland.

"Our study showed that despite international consensus guidelines, there are wide global variations in the way postmenopausal women are treated for early breast cancer,” said Professor van de Velde.

"We believe that there should be further efforts to ensure that women can all benefit from the most effective breast cancer treatment available, regardless of which country they live in."

Reference: British Journal of Surgery 2010; 97(5):671-697

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FDA Highlights - by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs OCTREOTIDE TREATS LIVER DISEASE CAUSED BY POLYCYSTIC KIDNEY DISEASE

R

esearchers report that sirolimusoctreotide, a hormone mimic, shows efficacy for polycystic liver disease (PLD) caused by autosomal dominant polycystic kidney disease (ADPKD), researchers report in recent issue of the Journal of the American Society of Nephrology.

This is the first US clinical trial testing octreotide in PLD. ADPKD can cause PLD, a condition leading to cysts in the liver. Octreotide mimics somatostatin, which regulates the secretion of some other hormones in the body. Somatostatin blocks both the formation of the chemical cyclic AMP and the secretion of fluids by cells, which appear play a role in the development of kidney and liver cystic diseases.

Marie Hogan, MD, Mayo Clinic College of Medicine, Rochester, Minnesota, and colleagues designed the study to test whether octreotide could shrink the cyst-filled livers of patients with PLD.

32

In the randomised, double-blind, placebocontrolled trial, they enrolled 42 patients with severe PLD caused by ADPKD (n = 34) or autosomal dominant PLD (n = 8). They treated subjects with octreotide or placebo, by monthly injections.

They reported that, after one year, liver volume decreased by an average of approximately 5% in patients taking octreotide, and it increased slightly (about 1%) in patients taking placebo.

Octreotide also affected the diseased kidneys of subjects with ADPKD, with total kidney volume remaining almost the same after 12 months in

‘

It remains essential

to continue monitoring acute gastroenteritis hospitalisation rates during subsequent

’

rotavirus seasons.

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the octreotide cohort, and increasing by more than 8% on average in the placebo group.

Both groups showed similar kidney function and octreotide was well tolerated.

"In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile," said Dr. Hogan.

VACCINE LOWERS HOSPITALISATIONS FOR PAEDIATRIC ACUTE GASTROENTERITIS

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esearchers have found that infant vaccination against rotavirus is associated with a significant decline in US hospitalisation rates for acute gastroenteritis. The findings appear in a recent issue of The Journal of Infectious Diseases.

Aaron T. Curns, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, and colleagues performed a large, retrospective study of US children aged younger than five years for hospitalisation due to acute gastroenteritis during a typical rotavirus season. They compared rates from 2000 to 2006, before the rotavirus vaccine was introduced, to 2007 to 2008, after its introduction.

They use hospital discharge data from 18 states with about 50% of the US population. They compared the median hospitalisation rates for gastroenteritis from all causes. They designated January through June as rotavirus season.

They found that hospitalisation rates for gastroenteritis were 16% lower in 2007 and 45% lower in 2008 compared with pre-vaccine rates.

During 2008, vaccinated infants aged 0 to 2 months showed a 28% reduction, while those aged 6 to 23 months showed a 50% reduction.

Among children aged 3 to 5 months and 24 to 59 months, the rates declined between 42% and 45%, respectively.

The investigators estimated that the vaccine prevented about 55,000 acute gastroenteritis

hospitalisations during the 2008 rotavirus season, with rates becoming one-half to two-thirds lower at periods, compared to previous seasons.

They also noted that declines in hospitalisations exceeded their estimates, occurring as well in age groups that were too young or too old to receive the vaccine - implying a "herd immunity" effect induced by peer-vaccination.

In an accompanying editorial, Geoffrey A. Weinberg, MD, and Peter G. Szilagyi, MD, University of Rochester School of Medicine & Dentistry, Rochester, New York, emphasised the importance of such real-world studies. "These encouraging findings are important for emphasising the benefits and increasing the acceptance of rotavirus vaccination in the United States and will also help other countries assess the value of rotavirus vaccines for their children," they wrote. "It remains essential to continue monitoring acute gastroenteritis hospitalisation rates during subsequent rotavirus seasons to fully understand and document the impact of vaccination as the programme matures in this country."

ZOLEDRONIC ACID/ CHEMO COMBO BEFORE BREAST SURGERY LOWERS TUMOUR CELL COUNT

Z

oledronic acid administered with chemotherapy for three months prior to breast cancer surgery reduces the number of women with tumour cells in their bone marrow at the time of surgery, investigators report in the recent issue of The Lancet Oncology.

"Bone marrow seems to be a DTC [disseminated tumour cells] sanctuary, allowing them to adapt and disseminate to different organs, where they're a leading cause of death," said lead author Rebecca Aft, MD, Alvin J. Siteman Cancer Center at BarnesJewish Hospital and Washington University School of Medicine, St. Louis, Missouri. "We believe that zoledronic acid inhibits the release of growth factors that help support the growth of DTCs." The authors noted that other recent studies have suggested that zoledronic acid improves disease-free survival when administered with oestrogen-lowering therapy before breast cancer surgery.

In this randomised, phase 2 study, the investigators divided 109 women with newly diagnosed stage II or stage III breast cancer into two cohorts. One cohort received chemotherapy montherapy, and the other received a combination of chemotherapy and zoledronic acid.

The investigators found that, after three months of treatment, the percentage of subjects with DTCs in their bone marrow decreased from 43% to 30% in the

‘

Zoledronic acid

improves disease-free

survival when administered with oestrogen-lowering therapy before breast

’

cancer surgery.

combination cohort and from 48% to 47% in the control group. They also reported that, among those women with no DTCs in their bone marrow at baseline, 87% remained negative after three months of combination treatment compared with 60% for chemotherapy monotherapy.

Zoledronic acid treatment with chemotherapy appeared to have other benefits. The investigators reported that subjects in the combination group showed significant gains in bone density after 12 months.

"Although it's common practice to administer zoledronic acid during chemotherapy given after breast cancer surgery, it isn't common when chemotherapy is given before surgery," said Dr. Aft. "Because chemotherapy increases bone loss, we would argue that women should receive zoledronic acid at the time of chemotherapy in the presurgical setting. Our single-institutional study also suggests that similar protocols using zoledronic acid for high-risk breast cancer patients should continue to be tested in larger, multi-institutional studies."

BOTULINUM INJECTION HELPS RELIEVE LATERAL EPICONDYLITIS

I

njected botulinum toxin relieves lateral epicondylitis, but requires the use of a careful, patient-specific injection-site method, researchers report in the recent issue of the Canadian Medical Association Journal.

Investigators from the Iman Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran conducted a randomised and controlled trial of 48 patients, determining the injection site based on each patient's forearm length.

All subjects had received prior therapeutic interventions which failed.

"We found that pain at rest and pain during maximum pinch were significantly reduced in patients with lateral epicondylitis after botulinum toxin was injected at the site, based on precise anatomic measurement of each patient's forearm length," authors wrote.

"However, this method caused a decline in maximum strength and resulted in extensor lag," they added.

In prior trials, which had failed, researchers performed injection at a fixed distance from anatomic landmarks.

The authors concluded that precise measurement to guide injection of botulinum toxin can be effective in the management of chronic lateral epicondylitis. However, it should be used for patients whose job does not require finger extension.

In a related commentary, Rachelle Buchbinder, MD, Monash University, Victoria, Australia, wrote that the high costs to an individual and society related to sick leave and disability from lateral epicondylitis means there is a clear need to identify the most costeffective therapies. However, she also noted, botulinum toxin might not be the right therapy for everyone, due to its potential effects on function, quality of life, and pain-free grip, as well as potential treatment-related partial loss of movement of the third and fourth fingers.

Sources: American Society of Nephrology, Infectious Diseases Society of America, Washington University School of Medicine and the Canadian Medical Association Journal

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by Steve Devrell

Breast cancer - A personal view

I

View from The Waiting Room

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attended a gym regularly, advice she was given in t is difficult to think of a disease that hospital. Jane says that as a result, she managed engenders more sympathy or even fear to get through her treatment without many side than breast cancer. It is high profile effects. The only real downside was the loss of because it is so devastating yet so common hair, but fortunately she loved all her wigs! in western society. I stress ‘western society’ Just six months after finishing her treatment because it is rare in many developing in 2007, another lump was detected. Having countries of the world where diet and already endured chemotherapy, radiotherapy lifestyle is so different from our own. It is and 12 months of Herceptin, Jane was back a fact that in China for example, where fighting the disease again. Her surgeon was a dairy products are rarely eaten, the great support, but she needed little persuasion incidence of breast cancer is only 1 in to go ahead with a double mastectomy and 100,000 (except in western tainted Hong opted for reconstruction to be done at the Kong where incidences is much higher). same time.

In China, breast cancer is referred to as Throughout her treatment, Jane felt she had the rich ladies’ disease. received incredible support Women in western from everyone at the society have a one in nine hospital, but she was chance of developing breast reluctant to have breast cancer. What is even more implants fitted because of alarming is the fact that the frequent reports of there are two particular ‘hot complications. Indeed the spots’ in the UK where only real complication she incidences of breast cancer has experienced with the are as high as 1 in 3 and surgery has been abscesses they are the comparatively caused by her implants. affluent towns of Watford Another course of and Solihull. chemotherapy followed A friend of mine called with the obligatory hair loss Jane, who lives in Solihull, – more wigs! She also was first diagnosed with underwent another 12 breast cancer in 1996. She months of Herceptin. was 38 at the time and had Jane Hollins was diagnosed with Because Jane’s treatment a five year old son. Her breast cancer three separate times was private, there was world fell apart for a while never an issue over prescribing the drug. She is and then, as she recovered, she gradually convinced that the prescribing of the drug has regained her confidence and optimism and felt saved her life on two occasions. Without the as if in her words, she ‘had got away with it!’ drug her survival rate was calculated at just one Since then she has been diagnosed with the in four, a survival rate that hadn’t changed for disease on a further two occasions. In 2004, 30 years. The postcode/economic lottery that just six weeks after her mother had been seems to decide the prescribing of this drug is, diagnosed with the same disease, another lump in Jane’s words, ‘A scandal! It is only when you was discovered. Within forty-eight hours, Jane are facing death that you realise the importance was in hospital feeling totally out of control and of life and in these circumstances, money has in desperate need of adopting a proactive very little to doing with the decision.’ approach to her situation.

At the moment, she is actively campaigning Soon after her treatment, she consulted a in her region for the mandatory prescribing of dietician/nutritionist. She decided to abstain from Herceptin for people in her situation. all dairy products and has maintained this strict Unfortunately the present economic climate is regime ever since. She tried to eat healthily and

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PRESCRIBING INFORMATION – UK AND ROI

one where blanket prescribing of this drug is becoming even less likely.

Now in 2010, Jane has recently moved from three to six month check-ups. This marks a personal and psychological boost for her, but she refuses to ask for a long term prognosis. She is determined to be positive and believes that the mind is a very powerful weapon in her armoury.

The pink ribbon is one of the most authoritative and instantly recognised symbols in our society. It evokes sympathy amongst non sufferers and a sense of strong camaraderie amongst those who are fighting the disease. It is that sense of camaraderie that seems to give strength.

Race for Life and Walk the Walk are well known examples of fund raising activities that have become almost obligatory for

‘

Unfortunately the present economic climate is one where blanket prescribing of this drug [Herceptin] is becoming even less likely.

’

breast cancer sufferers and sympathisers.

That camaraderie seems to be a key ingredient amongst most sufferers and many view these groups as important in their own personal coping mechanism. The self-help groups provide a valuable source of strength for many breast cancer sufferers. Jane was invited to join a local self-help group with the rather twee title of Breast Friends. This Sutton Coldfield group is run by unpaid volunteers who have all been diagnosed with breast cancer and have undergone surgery. There is also a group for younger members and mums who have been diagnosed with breast cancer. This group called Pink Orchids, offers the opportunity to chat with people in a similar situation. The meetings offer talks from various people including beauty consultants and representatives from bra and swimwear companies.

A quick look on the internet shows that these self-help groups exist all over the country and indeed, all over the world; no one should feel isolated. In the US, where their psyche is perhaps somewhat different

to the more reserved UK, there seems to be almost an obligatory desire to join and the membership and cohesion of these groups is particularly strong.

Further research on the internet shows that there are pages and pages of advice, publications and personal experiences that cover the subject of breast cancer, including some with extremely positive titles like Survive Breast Cancer – 11 steps to winning the battle. Internet users can also log on to many national and international chat rooms for sufferers of breast cancer. The Breast Cancer Care website comes in for much praise for its comprehensive coverage and support. It contains detailed information and guidelines for the disease as well as a 24 hours interactive chat room.

The recurring pattern of attitude from breast cancer sufferers is an initial traumatic shock. One moment you are well, happy confident and in a flash, your cancer diagnosis causes confusion, depression and completely wrecks your life. Patients start to ask questions of themselves, like ‘What do I do now?’ and ‘Where did I go wrong?’

Confidence is lost with a once fit and healthy person suddenly facing the prospect of radical and invasive surgery.

Breast cancer sufferers have remarked on how they have to make adjustments to relationships with their family and spouse and to adopt new exercise and dietary regimes. The overriding opinion that comes through from the testimonies of breast cancer sufferers is that it is a lifelong, lifechanging experience.

The good news though is that breast cancer sufferers are surviving so much longer and in greater numbers that there is a call for hospitals to open departments devoted to survivorship and in the USA, the National Cancer Institute has launched a special research area dedicated to studying what it means to survive cancer.

Breast cancer is one of the most widely researched areas of cancer. There is a great deal of support for sufferers out there. It is up to the individual as to how much they want to seek that support. You may enjoy the corporate camaraderie of associating with fellow sufferers, or you may, like Jane, prefer to make it a personal crusade and rely solely on the advice of experts. Either way, the fact that breast cancer is one of the most high profile diseases in the western world means someone is on your case!

REBIF ® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 8.8 MICROGRAMS/0.1ML AND REBIF ® 22 MICROGRAMS/0.25ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF ® 22 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF ® 44 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE Interferon beta-1a Presentation Rebif 8.8μg and 22μg: Pre-filled glass syringe containing 8.8μg or 22μg of Interferon beta-1a in respectively 0.2 or 0.5ml. Rebif 22μg or 44μg: Pre-filled glass syringe containing 22μg or 44μg Interferon beta-1a in 0.5ml.

Rebif 8.8μg/0.1ml and Rebif 22μg/0.25ml: Pre-filled glass cartridge containing 132μg of Interferon beta-1a in 1.5ml. Rebif 22μg/0.5ml or Rebif 44μg/0.5ml: Pre-filled glass cartridge containing 66μg or 132μg of Interferon beta-1a in 1.5ml. Indication Treatment of relapsing multiple sclerosis. Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity. Dosage and administration Initiate under supervision of a physician experienced in the treatment of multiple sclerosis. Administer by subcutaneous injection. Recommended dose: Weeks 1 and 2: 8.8μg three times per week (TIW); weeks 3 and 4: 22μg TIW; week 5 onwards: 44μg TIW (22μg TIW if patients cannot tolerate higher dose). Rebif solution for injection in cartridge is for multidose use and should only be used with the RebiSmart autoinjector device following adequate training of the patient and/or carer. Follow the instructions provided with the RebiSmart device. Limited published data suggest that the safety profile in adolescents aged 12–16 years receiving Rebif 22 TIW is similar to that in adults. Do not use in patients under 12 years of age. Prior to injection and for 24h afterwards, an antipyretic analgesic is advised to decrease flu-like symptoms. Evaluate patients at least every second year of the treatment period.

Contraindications History of hypersensitivity to natural or recombinant interferon beta, or to any of the excipients; treatment initiation in pregnancy; current severe depression and/or suicidal ideation. Precautions Inform patients of most common adverse reactions. Use with caution in patients with previous or current depressive disorders and those with antecedents of suicidal ideation. Advise patients to report immediately any symptoms of depression and/or suicidal ideation. Closely monitor patients exhibiting depression and treat appropriately. Consider cessation of therapy. Administer with caution in patients with a history of seizures and those receiving anti-epileptics, particularly if epilepsy is not adequately controlled. Closely monitor patients with cardiac disease for worsening of their condition during initiation of therapy. Patients should use an aseptic injection technique and rotate injection sites to minimise risk of injection site necrosis. If breaks in skin occur, patients should consult their doctor before continuing injections. If multiple lesions occur, discontinue Rebif until healed. Use with caution in patients with history of significant liver disease, active liver disease, alcohol abuse or increased serum ALT. Monitor serum ALT prior to the start of therapy, at months 1, 3 and 6 and periodically thereafter. Stop treatment if icterus or symptoms of liver dysfunction appear. Treatment has potential to cause severe liver injury including acute hepatic failure. Full haematological monitoring is recommended at months 1, 3 and 6 and periodically thereafter. All monitoring should be more frequent when initiating Rebif 44μg. New or worsening thyroid abnormalities may occur. Thyroid function testing is recommended at baseline and if abnormal every 6–12 months.

Use with caution in, and closely monitor patients with, severe renal and hepatic failure or severe myelosuppression. Serum neutralising antibodies may develop and are associated with reduced efficacy. If a patient responds poorly and has neutralising antibodies, reassess treatment. Use with caution in patients receiving medicines with a narrow therapeutic index cleared by cytochrome P450. Women of childbearing potential should use effective contraception. Limited data suggest a possible increased risk of spontaneous abortion. During lactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and give supportive treatment. Side effects In the case of severe or persistent undesirable effects, consider temporarily lowering or interrupting dose. Very common: flu-like symptoms, injection site inflammation/reaction, headache, asymptomatic transaminase increase, neutropenia, lymphopenia, leucopenia, thrombocytopenia, anaemia. Common: injection site pain, myalgia, arthralgia, fatigue, rigors, fever, pruritus, rash, erythematous/maculo-papular rash, diarrhoea, vomiting, nausea, depression, insomnia, severe elevations of transaminase.

Serious side effects include: injection site necrosis, hepatitis with or without icterus, severe liver injury, anaphylactic reactions, angioedema, erythema multiforme, erythema multiforme-like skin reactions, seizures, thromboembolic events, thrombotic thrombocytopenic purpura/haemolytic uremic syndrome, suicide attempt, Stevens-Johnson syndrome, dyspnoea, retinal vascular disorders. Consult the Summary of Product Characteristics for more information relating to side effects. Legal category POM. Price Rebif 8.8μg and 22μg: 6 (0.2ml) + 6 (0.5ml) syringes – £552.19; Rebif 22μg: 12 syringes (0.5ml) – £624.77; Rebif 44μg: 12 syringes (0.5ml) – £813.21; Rebif 8.8μg/0.1ml and 22μg/0.25ml: 2 cartridges – £406.61; Rebif 22μg/0.5ml: 4 cartridges – £624.77; Rebif 44μg/0.5ml: 4 cartridges – £813.21; For prices in Ireland, consult distributors Allphar Services Ltd. Marketing Authorisation Holder and Numbers Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/98/063/007; 003; 006; 010; 008; 009. For further information contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: 020 8818 7373. Republic of Ireland: Merck Serono, 3013 Lake Drive, Citywest Business Campus, Dublin 24. Tel: 01 4661910.

Date of Preparation January 2010.

Date of Preparation: March 2010

REB10–0057

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

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

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

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. In the Republic of Ireland information can be found at www.imb.ie. Adverse events should also be reported to Merck Serono Limited - Tel: +44(0)20 8818 7373 or email: medinfo.uk@merckserono.net.

Rebif : established, effective treatment for people with relapsing– remitting multiple sclerosis (RRMS)1,2 ®

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

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

DMD: disease-modifying drug. sc: subcutaneous. tiw: three times weekly. im: intramuscular. qw: once weekly.

Prescribing information can be found overleaf.