Evidentia Nov/Dec 2011

Volume 5 Issue 6 | November/December 2011 | ISSN 1753-464X

Overweight children have three times the risk of high blood pressure

Number of people with diabetes has reached a staggering 366 million worldwide Emissions from livestock farms cause greater exacerbations in COPD and asthma patients

Conference reports from: Amsterdam, Lisbon and Stockholm

Aspirin halves hereditary cancer risk

Control and care matter Trajenta® – suitable for your hyperglycaemic adult type 2 diabetes mellitus patients as monotherapy in metformin-inappropriate patients and add-on to metformin alone or metformin + sulphonylurea1

Efficacy – significant HbA

1c

reductions versus placebo2–4

– HbA1c reduction sustained over 102 weeks as add-on to metformin + sulphonylurea5

Generally well tolerated – Trajenta , studied in over 4,000 patients in clinical trials, ®

has an overall incidence of adverse events that is similar to placebo1

Different – the first one dose, once daily DPP-4 inhibitor excreted primarily via the bile: no dose adjustment required

Prescribe – Trajenta

®

1,6–11

1

5 mg once daily1

TRAJENTA® 5 mg film-coated tablets Prescribing Information (UK) Film-coated tablets containing 5 mg linagliptin. Indication: Trajenta is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults: as monotherapy - in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to intolerance, or contraindicated due to renal impairment; as combination therapy: - in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control; - in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. Dose and Administration: 5 mg once daily. If added to metformin, the dose of metformin should be maintained and linagliptin administered concomitantly. When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.

Patients with renal impairment: no dose adjustment required. Pharmacokinetic studies suggest that no dose adjustment is required for patients with hepatic impairment but clinical experience in such patients is lacking. Elderly: no dose adjustment is necessary based on age however, clinical experience in patients > 75 years of age is limited. The safety and efficacy of linagliptin in children and adolescents has not yet been established. No data are available. Trajenta can be taken with or without a meal at any time of the day.

If a dose is missed, it should be taken as soon as possible but a double dose should not be taken on the same day. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Trajenta should not be used in patients with type 1 diabetes

or for the treatment of diabetic ketoacidosis. Caution is advised when linagliptin is used in combination with a sulphonylurea; a dose reduction of the sulphonylurea may be considered. Interactions: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin is a P-glycoprotein substrate and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates. The risk for clinically meaningful interactions by other medicinal products on linagliptin is low and in clinical studies linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin or oral contraceptives (please refer to Summary of Product Characteristics for information on clinical data). Fertility, pregnancy and lactation: Avoid use during pregnancy. A risk to the breast-fed child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Trajenta therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

No studies on the effect on human fertility have been conducted for Trajenta.

Undesirable effects: Adverse reactions reported in patients who received linagliptin 5 mg daily as monotherapy or as add-on therapies (pooled analysis of placebo-controlled studies). The adverse reactions are listed by absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to

< 1/1,000), or very rare (<1/10,000), not known (cannot be estimated from the available data). Very common: hypoglycaemia (combination with/ add on to metformin and sulphonylurea). Uncommon: nasopharyngitis (monotherapy; combination with/add on to metformin); hypersensitivity (combination with/add on to metformin); cough (monotherapy; combination with/add on to metformin). Not known: nasopharyngitis (combination with/add on to metformin and sulphonylurea); hypersensitivity (monotherapy; combination with/add on to metformin and sulphonylurea); cough (combination with/add on to metformin and sulphonylurea); pancreatitis (monotherapy; combination with/add on to metformin; combination with/add on to metformin and sulphonylurea). Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes and NHS price: 28 tablets £33.26. Legal category: POM. MA number: EU/1/11/707/003. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Prepared in September 2011.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk.

Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone).

References: 1. Trajenta® Summary of Product Characteristics, August 2011. 2. Barnett AH et al. Poster No. 823-P. The European Association for the Study of Diabetes 46th Annual Meeting, 20–24 September 2010, Stockholm, Sweden. 3. Taskinen M-R et al. Diabetes Obes Metab 2011;13:65–74. 4. Owens DR et al. Diabet Med 2011. Accepted manuscript online, DOI: 10.1111/j.1464–5491.2011.03387.x. 5. Boehringer Ingelheim, data on file LIN11-06.

6. Vincent SH et al. Drug Metab Dispos 2007;35:533–538. 7. Januvia (sitagliptin) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/EMC/medicine/19609/SPC/JANUVIA+100mg+film-coated+tablets/ (accessed September 2011). 8. Galvus (vildagliptin) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/EMC/medicine/20734/SPC/Galvus+50+mg+Tablets/ (accessed September 2011). 9. Onglyza (saxagliptin) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/EMC/medicine/22315/SPC/Onglyza+2.5mg+%26+5mg+film-coated+tablets/ (accessed September 2011). 10. Deacon CF. UK/TRJ/00091g Date of preparation: September 2011 Diabetes Obes Metab 2011;13:7–18. 11. Blech S et al. Drug Metab Dispos 2010;38:667–678.

Bringing clinical evidence to practice in primary and secondary care

Contents 4

COVER STORY

Guest Editorial by Dr. Sarah Jarvis Statins and diabetes - More harm than good?

Volume 5 Issue 6 | November/December 2011 | ISSN 1753-464X

6

Combination therapy rids common infection from implanted medical devices

8

Obesity and Type 2 diabetes: What’s similar and what’s different?

Fungal infections

Overweight children have three times the risk of high blood pressure

Reports from the EASD meeting, Lisbon

11

Nearly half the world’s adults will experience LUTS by 2018

12

The rivalry between cisplatin and carboplatin goes on: BTOG 2 trial

16

Chronic, non-cancer pain treatments are sub-optimal in most patients

18

Identification and management of breakthrough cancer pain remains a challenge

20

Stroke prevention clinics reduce one-year mortality rates by over 25%

22

Considerably lower risk of stent thrombosis and restenosis in 'new generation' drug-eluting stents

24

Environmental health risks of livestock farming

27

EMA Highlights

28

The BIG FOUR

30

World Health Matters

32

FDA Highlights

34

View from The Waiting Room

Number of people with diabetes has reached a staggering 366 million worldwide

Urology report

Emissions from livestock farms cause greater exacerbations in COPD and asthma patients

Conference reports from: Amsterdam, Lisbon and Stockholm

Aspirin halves hereditary cancer risk

21 Overweight children have

World Conference on Lung Cancer

three times the risk of high blood pressure

Back pain

16

Reports from the EMCC, Stockholm

Cardiology reports

21

Reporting from the ESC Congress, Paris

Reports from the ERS Annual Congress, Amsterdam

22

Emerging uses of EMA approved drugs

Reporting from some of the latest journal articles

Medical news from around the world

Emerging uses of FDA-approved drugs

35

Dying to live for ever EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

3

Guest editorial

by Dr. Sarah Jarvis

Statins and diabetes More harm than good?

I

T HAD TO HAPPEN. Sooner or later, all too many fairytale stories become victims of their own success, and statins are no exception. In less than 20 years, statins have appeared on the horizon, become the answer to every maiden’s prayer and the panacea to all cardiometabolic ills. They are now charged with causing diabetes, one of the highest risk factors for the very conditions they are supposed to prevent.

It all started with the 4S study, which revealed a 34% relative risk reduction (RRR) for major cardiovascular (CV) events, 42% RRR in coronary mortality and 30% RRR in total mortality in patients with a history of angina or myocardial infarct taking statins.1 Hot on its heels came the WOSCOPS study in primary prevention patients at high risk of CVD, which offered a RRR of 31% in coronary events and 32% in CV mortality, albeit just missing statistical significance for total mortality with a 22% RRR and a P value of 0.051.2 In 2004, the Heart Protection Study showed that 5 years of statin treatment would prevent one major vascular event for every 10 patients with prior MI and every 13 people with diabetes treated. But what singled this study out was the finding that the same benefit was achieved regardless of pre-treatment cholesterol level (1/3 of people in the trial had a pre-treatment LDL cholesterol below 3mmol/l), age, gender or other treatment.3 Effectively, this study ensured that statin treatment for secondary prevention became effectively mandatory, and was quickly

Contributors: Thomas R. Collins, Steve Devrell, Gary Finnegan, Peter Mas-Mollinedo, Samuel Peters, Dr. Sarah Jarvis, Bruce Sylvester

incorporated into national guidance.4 The only debate was how low to go – while the Joint British Societies advocated targets of four and two for total and LDL cholesterol respectively for secondary prevention and indeed for all patients

Over this period, more studies focused on the possible benefits of statin treatment in patients with diabetes, long known to be at high risk of CV disease.7

at high risk of CVD from 2005, the National Institute for Clinical Excellence effectively demurred from setting any target for total or LDL cholesterol until 2010, when it recommended intensification of statin treatment in secondary prevention if targets of four and two were not reached.5,6 Over this period, more studies focused on the possible benefits of statin treatment in patients with diabetes, long known to be at high risk of CV disease.7 The CARDS study, looking at atorvastatin treatment in patients with diabetes but no history of CVD, showed a 37% relative risk reduction for major CV events, translating

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

ICR (UK) PUBLISHING

International Conference Reports

into a numbers needed to treat (NNT) of 27 over four years to prevent one major CV event.8 As a result of this and other studies, NICE guidance on diabetes recommended targets of four and two for total and LDL cholesterol respectively for all patients with diabetes at ‘high risk of CVD’, which included the vast majority of patients with Type 2 diabetes.9 But all drugs have side effects. 33% of patients in the Heart Protection Study reported muscle pain or weakness at some point during the study, although interestingly the figure was no different from the placebo group and only 0.5% of patients discontinue treatment as a direct result.3 Myalgia is a well recognised side effect of statins, but this was considered a small price to pay for such dramatic improvements in morbidity and mortality.

In 2008, the JUPITER study in primary prevention patients was stopped prematurely on the grounds of overwhelming benefit in the rosuvastatin arm, with the statin showing 44% RRR in major CV events, 48% RRR in stroke and 20% RRR in overall mortality.10 However, the incidence of new onset diabetes was 25% higher in the active treatment arm, and as a result attention turned to signals for new onset diabetes in other statin trials.

In 2010, a meta-analysis of studies including over 90,000 patients without diabetes showed a 9% increase in the incidence of new onset diabetes among statin treated patients. The risk of developing diabetes was highest in trials with older participants, but no link was found between LDL-cholesterol reduction or baseline

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ICR-UK & sister company IMI, publish a number of medical jour nals and electronic jour nals. For more information visit www.icr-uk.com ICR-UK are affiliate members of the ABPI ISSN: 1753-464X Designed by JAM Design 01483 426017 P r i n t e d b y S t e p h e n s & G e o r g e 0 1 6 8 5 3 8 8 8 8 8 D i s t r i b u t e d b y P r e c i s i o n M a r k e t i n g G r o u p 0 1 2 8 4 7 1 8 9 0 0

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EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

body mass index and risk of developing diabetes. The meta-analysis showed a NNT of 225 for four years’ treatment with statins to cause one extra case of diabetes.11 In early 2011, Cochrane weighed into the risk-benefit debate with a review of 14 primary prevention statin trials involving 34,000 patients, concluding that ‘only limited evidence showed that primary prevention with statins may be cost-effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.’ They did conclude that all cause mortality was reduced by 16% and combined fatal and non fatal CVD endpoints by 30%, but highlighted the lack of reporting of potential adverse events (apart from cancer or muscle pain, which were not increased) and the high NNT of 1000 patients for one year to prevent one death.12 This appeared directly to contradict a 2010 meta-analysis by the Cholesterol Triallists’ Collaboration, which suggested that in any patient at high CVD risk (about 20% over 10 years), the message for LDL-cholesterol was ‘lower is better’.13 To confuse matters further, the most recent review of the literature on statins and diabetes (involving 32,752 patients) suggests a direct correlation between intensity of cholesterol lowering with high dose statins and new onset diabetes – compared with moderate dose statins, high dose statins increased the risk by 12%,14 with a NNT for one year of 498 to cause

one new case of diabetes.

But what does it all mean in practice? That very much depends on your perspective. For patients who already have diabetes or a history of CVD, nobody is disputing the fact that the benefits of intensive lipid lowering with statins hugely outweigh the risks. For patients at high risk of CVD, overall mortality reductions have been consistently shown – effectively suggesting that by taking statins they are less likely to die but more likely to live on with diabetes. Even with high dose statins, the absolute increased risk of diabetes is small – but for lower risk patients, it may be a risk they prefer not to take.

Statins for the prevention of cardiovascular events.

NICE technology Appraisal 94. London: NICE, 2006 6. National Institute for Health and Clinical Excellence.

Lipid modification. NICE clinical guideline 67 London: NICE, 2006 7. Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care 1979; 2:120–126 8. Colhoun H, Betteridge D, Durrington P, et al on behalf of the CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in Type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685– 96 9. National Institute for Health and Clinical Excellence.Type 2 diabetes: newer agents . NICE

References:

clinical guideline 87 London: NICE, 2009

1. Scandinavian Simvastatin Survival Study Group.

Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the

10. Ridker P, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. NEJM 2008; 359(21): 2195-207

Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383–1389

11. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of

2. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group.

randomised statins trials. Lancet 2010; 375: 735-742 12. Taylor F, Ward K, Moore THM, et al. Statins for the

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333:1301-1307

primary prevention of cardiovascular disease.

Cochrane Database Syst Rev 2011; 1(CD004816) 13. Cholesterol Treatment Trialists' (CTT) Collaboration.

3. Heart Protection Study Collaborative Group.

Efficacy and safety of intensive LDL-cholesterol-

MRC/BHF Heart Protection Study of cholesterol

lowering therapy: A meta-analysis of data from 170

lowering with Simvastatin in 20,536 high-risk

000 participants in 26 randomised trials. Lancet

individuals: a randomised placebo controlled trial.

2010; DOI:10.1016/S0140-6736(10)61350-5.

Lancet 2002; 360: 7-22

Available at: http://www.thelancet.com.

4. Joint British Societies’ Guidelines on Prevention of

14. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident

Cardiovascular Disease in Clinical Practice. Heart

diabetes with intensive-dose compared with

2005; 91(Suppl): v1-v52

moderate-dose statin therapy. JAMA 2011; 305:

5. National Institute for Health and Clinical Excellence.

2556-2564

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EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

5

Fungal infections

Combination therapy rids common infection from implanted medical devices

R

ESEARCHERS AT THE University of Toronto have developed a therapy for a potentially deadly type of infection common in catheters, artificial joints and other "in-dwelling" medical devices. Their findings appear in the Open Access Journal PLoS. The therapy targets fungal infections, which are hard to treat in such devices because they are composed of biofilms - complex groupings of cells that attach to surfaces. Biofilms, in turn, are coated in a gooey matrix that resists drugs.

Patients often undergo surgical removal of the infected catheter or other device in an attempt to clear the disease and prevent a system-wide dispersal of infecting cells.

In this study, researchers showed that inhibiting the function of a protein called Hsp90 abolishes

drug resistance in the two main fungal pathogens of humans, Candida albicans and Aspergillus fumigatus. "It takes classic antifungals, which were not effective against biofilms, and makes them very effective," said Professor Leah Cowen, principal investigator on the study who holds the Canada Research Chair in Microbial Genomics and Infectious Disease at University of Toronto's Department of Molecular Genetics.

In an animal model of a central venous catheter infected with deadly fungus, the researchers were able to completely clear the infection by inhibiting Hsp90 and applying antifungals.

Fungal pathogens are a major clinical problem.

Candida albicans is the third-leading cause of intravascular catheter-related infections, and is fatal in about 30% of infections associated with

devices. And the number of acquired fungal bloodstream infections has increased by more than 200% over the last two decades, partly because successful treatments for previously fatal diseases like cancer and AIDS have left many patients immunocompromised and susceptible to infection.

With more than 10 million patients per year now receiving catheters, artificial joints and other devices, there is a pressing need for a better understanding of biofilms and their role in drug resistance of fungal pathogens.

For further information contact: Jim Oldfield jim.oldfield@utoronto.ca COMPETING INTERESTS: The authors have declared that no competing interests exist.

To see full report go to http://dx.plos.org/10.1371/journal.ppat.1002257

Fatal fungal infections resist newest class of drugs

F

UNGI THAT CAUSE severe infections in those with compromised immune systems are resisting the action of the latest group of antifungal drugs. Uncovering their strategies for doing this will lead to more effective treatments, says a scientist speaking at the Society for General Microbiology's Autumn Conference at the University of York.

Candida albicansis the most common hospitalacquired fungal infection and can cause illness by sticking to and colonising plastic surfaces implanted in the body such as catheters, cardiac devices or prosthetic joints. From there the fungus can spread through the bloodstream to the major organs. While normally harmless to healthy individuals, C. albicans can cause fatal infections in immunocompromised people such as those suffering from cancer, trauma and organ transplantation.

Fungi such as C. albicans are covered in a sugar-rich outer layer (cell wall) that protects the fungus from the environment. The newest class

6

of antifungal drugs, the echinocandins, targets the enzyme that makes one of the two key sugar polymers found in the cell wall, called betaglucan. Scientists at the University of Aberdeen are investigating how C. albicans responds to echinocandins and have shown how the fungus is able to change the structure of its cell wall to render the drug ineffective.

Dr. Carol Munro who is leading the research along with Professor Neil Gow explained, "If levels of drug are used that do not kill the fungus straight away, C. albicans responds by producing an excess of the other key cell wall sugar polymer, called chitin. Fungal cells displaying higher levels of chitin can survive treatment with echinocandins, allowing infection to progress."

Echinocandins are given by IV injection and have a relatively broad spectrum of activity against most Candida species. The increasing number of reports of sporadic breakthrough infections in patients receiving echinocandin therapy is

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

worrying, explained Dr. Munro. "Echinocandins are used to treat Candida infections that may already be resistant to the azole group of antifungals. Healthcare specialists must be made aware of the potential problems and should keep up to date with the results of global surveillance programmes reported in the specialist literature."

The group's work will help improve treatment options for patients who experience antifungal failure. "Understanding the mechanisms of drug resistance will help us determine when it is appropriate to switch to a different drug regime.

Our work so far suggests that the use of drugs that inhibit the production of chitin (if they were available), in combination with echinocandins, would improve treatment effectiveness for Candida infections," said Dr. Munro. This work therefore, also impacts on the development of much needed novel antifungal therapies.

For further information contact: Laura Udakis l.udakis@sgm.ac.uk

Right treatment. Right time.

Immunocompromised patients can’t afford to wait. Vfend® offers superior efficacy and survival in the treatment of invasive aspergillosis vs amphotericin B at week 12.1 Vfend® IV has the highest evidence rating for first‑line treatment2 of this life-threatening infection and is available at the lowest daily treatment cost compared to caspofungin or AmBisome®.3

Anti-Infectives

Efficacy WHEN IT MATTERS MOST VFEND® (voriconazole) ABBREVIATED PRESCRIBING INFORMATION - UK Please refer to the SPC before prescribing Vfend Film-coated Tablets or Vfend Powder for Solution for Infusion or Vfend Powder for Oral Suspension.

Presentation: White to off-white film-coated tablets, containing either 50mg or 200mg voriconazole; powder for solution for infusion (IV) containing 200mg voriconazole; powder for oral suspension containing 40mg/ml voriconazole when constituted. Indications: Treatment of invasive aspergillosis. Treatment of candidaemia in non-neutropenic patients. Treatment of fluconazoleresistant serious invasive Candida infections (including C. krusei). Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.

Vfend should be administered primarily to patients with progressive, possibly life-threatening infections. Administration & dosage: After reconstitution and dilution, administer the IV infusion at a maximum recommended rate of 3mg/kg per hour over 1 to 2 hours. Take Vfend tablets at least one hour before, or one hour following, a meal. Take Vfend oral suspension at least one hour before, or two hours following a meal. On the basis of the high oral bioavailability (96%), switching between IV and oral administration is appropriate when clinically indicated. Treatment duration should be as short as possible depending on the patients’ clinical and mycological response.

Duration of IV treatment should not exceed 6 months.

Adults and adolescents (aged 12 to 16 years): IV: a loading dose of 6mg/kg every 12 hours (for the first 24 hours) followed by a maintenance dose of 4mg/kg twice daily. Orally: Patients 40kg and above - a loading dose of 400mg (10ml) every 12 hours (for the first 24 hours), followed by a maintenance dose of 200mg (5ml) twice daily. Patients less than 40kg - a loading dose of 200mg (5ml) every 12 hours (for the first 24 hours), followed by a maintenance dose of 100mg (2.5ml) twice daily. Children (aged 2 to <12 years): Loading dose not required. IV maintenance dose 7mg/ kg twice daily; Oral maintenance dose 200mg twice daily (oral suspension formulation recommended). Not studied in paediatric patients with hepatic or renal insufficiency or those aged less than 2 years. IV administration is recommended in children with malabsorption or very low body weight for age as oral bioavailability may be limited. Elderly: No dose adjustment.

Renal impairment (moderate to severe - creatinine clearance <50ml/min): No dose adjustment. Oral administration recommended as accumulation of IV vehicle, SBECD, occurs. Hepatic impairment (mild to moderate - Child-Pugh A and B): Use standard loading dose regimen and halve maintenance dose. Vfend has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C). Contra-indications: Known hypersensitivity to voriconazole or to any of the excipients; co-administration with ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, quinidine,

rifampicin, carbamazepine, phenobarbital, sirolimus, high dose ritonavir (≥400mg twice daily) and St John’s Wort. Pregnancy: Avoid unless benefit outweighs risk to foetus. Lactation: Stop breast-feeding when starting Vfend. Warnings and precautions: Use with caution in patients with hypersensitivity to other azoles and in patients with potentially proarrhythmic conditions. QT interval prolongation and torsades de pointes reported rarely in patients with other risk factors. Monitor and correct electrolyte disturbances prior to initiation and during Vfend therapy. Infusion-related reactions, predominantly flushing and nausea, and anaphylactoid-type reactions have been observed. Monitor hepatic function when starting Vfend and routinely in patients who develop abnormal LFTs. Liver dysfunction is usually reversible on stopping Vfend. In clinical trials there were uncommon reports of serious hepatic reactions, primarily in patients with serious underlying medical conditions. Monitor renal function as patients are likely to be on concomitant nephrotoxic medications or have underlying conditions that affect renal function. Monitor pancreatic function in patients (especially children) with risk factors for acute pancreatitis such as recent chemotherapy or HSCT. Dermatological reactions (mild or moderate rash) are common. There have been rare reports of serious cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and discoid lupus erythematosis. In patients who develop a rash, stop Vfend if lesions progress. Vfend has been associated with phototoxicity and pseudoporphyria.

Advise patients to avoid sunlight exposure and use protective clothing and sunscreen. Skin squamous cell carcinoma (SCC) has been reported during long term therapy (>6 months) in patients with phototoxicity and additional risk factors including immunosuppression. Consider stopping Vfend if a patient develops a skin lesion consistent with SCC. There have been rare reports of prolonged visual adverse events, including blurred vision, optic neuritis and papilloedema. Avoid co-administration of phenytoin, rifabutin and low dose ritonavir (100mg twice daily) unless the benefit outweighs the risk. Monitor for methadone toxicity (including QTc prolongation) if co-administering with Vfend.

Co-administration with efavirenz requires dose adjustment of both products.

Consider reducing the dose of any co-administered short acting (alfentanil, fentanyl, sufentanil) and long acting opiates (oxycodone, hydrocodone) which are CYP3A4 substrates. Frequent monitoring of opiate-associated adverse events may be necessary (including a longer respiratory monitoring period). If voriconazole is used sequentially after fluconazole, monitor for voriconazole associated adverse events. Excipient information: Vfend IV contains sulphobutylether beta cyclodextrin sodium (SBECD) and 217.6mg of sodium per vial. Vfend tablets contain lactose, Vfend oral suspension contains sucrose. Incompatabilities: Vfend IV is not compatible with 4.2% sodium bicarbonate infusion. Do not infuse Vfend IV into the same line with other

IV products or at the same time as any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines. Vfend IV and TPN may be infused simultaneously but through separate lines. Drug interactions: Voriconazole is metabolised by and also inhibits the cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4. Medicines that inhibit, induce or are metabolised by these isoenzymes may increase, decrease or have no effect on voriconazole plasma levels and vice versa. Some interactions can be managed by dose adjustment and careful clinical and/or biological monitoring. See SPC. Side-effects: Very common (frequency ≥1/10) adverse effects in clinical studies were visual disturbances including blurred vision, chromatopsia and photophobia, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema and abdominal pain, generally of mild to moderate severity. Visual disturbances (in 30% of subjects) were mild, transient and fully-reversible with no clinically significant long-term sequelae. Patients experiencing visual symptoms must avoid potentially hazardous tasks e.g. driving or operating machinery. Also dermatological, hepatic, infusion-related reactions and post-marketing reports of pancreatitis in paediatric patients (see precautions above). Altered taste-perception reported with Vfend oral suspension. See SPC for other side effects. Legal category: POM. Basic NHS cost: Pack of 28, 50mg tablets [EU/1/02/212/005] £275.68; Pack of 28, 200mg tablets [EU/1/02/212/017] £1,102.74; 30ml vial of 200mg Powder for Intravenous Infusion [EU/1/02/212/025] £77.14; 100ml bottle of 40mg/ml powder for oral suspension [EU/1/02/212/026] £551.37. 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: January 2011. Ref: VF 14_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 References 1. Herbrecht R et al. Voriconazole vs amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 6:408–415.

2. Herbrecht R et al. Antifungal therapy in leukemia patients 2009 update of the ECIL1 and ECIL2 guidelines. 3rd European Conference on Infections in Leukemia.

September 2009, Juan-le-Pins, France. Accessed online March 2010.

3. MIMS August 2011.

Date of preparation: September 2011 VFE1275d

European Association for the Study of Diabetes Reports from the EASD meeting, Lisbon by Bruce Sylvester

Obesity and Type 2 diabetes: What’s similar and what’s different?

A

S PART OF the EASD/ADA Symposium, presentations by Professor Steven E. Kahn (VA Puget Sound Health Care System and University of Washington in Seattle, Washington, USA), Robert H. Eckel (University of Colorado Medical Campus, Aurora, Colorado, USA), and David M. Nathan (Harvard Medical School, Boston, MA, USA) discussed the findings of an expert international working group that has investigated common pathways to obesity and Type 2 diabetes.

The prevalence of obesity and Type 2 diabetes is increasing rapidly around the world. The international working group consisted of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or Type 2 diabetes, and their meeting was co-sponsored by the European Association for the Study of

Diabetes, The Endocrine Society, and the American Diabetes Association. Participants reviewed and discussed published literature and their own unpublished data in order to reach consensus on recommendations for future needs in research and clinical care of obesity and Type 2 diabetes.

They concluded that the major questions linking obesity to Type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include: 1. Why don’t all patients with obesity develop Type 2 diabetes?

2. Through what mechanisms do obesity and insulin resistance contribute to ß-cell decompensation and if/when obesity prevention ensues, how much reduction in Type 2 diabetes incidence will follow?

3. How does the duration of Type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight loss drugs and/or bariatric surgery on ß-cell function and glycaemia?

4. What is necessary for regulatory approval of medications and possibly surgical approaches for preventing Type 2 diabetes in patients with obesity?

“Improved understanding of how obesity relates to Type 2 diabetes may help advance effective and cost-effective interventions for both conditions, including more tailored therapy,” says Kahn. “To expedite this process, it was recommended that further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacologic and surgical management was required,” he concludes.

Controversies in gestational diabetes

I

N HIS LECTURE “Should we Treat Mild Gestational Diabetes?”, Robert Fraser (University of Sheffield, UK) says that interventions such as a low glycaemic index (GI) diet, and supplementary oral hypoglycaemic agents (OHA) such as glibenclamide or metformin if indicated, represent an effective and cost-effective way of reducing the likelihood of complications of this commonlyencountered problem with pregnancy, as well as the need for insulin. Metformin can further provide additional benefits in terms of helping obese women reduce the net fat gain which commonly accompanies pregnancy.

Gestational diabetes (GDM) affects between 2% and 5% of pregnancies in the UK but the proportion is rising as part of a worldwide trend.

Much higher rates may be seen in countries where obesity and relatively later ages at reproduction are common and ethnic origin may

8

be a factor in determining individual risk.

Screening in the UK should be universal and based on risk factors, but practice is patchy.

However, treatment is usually of a good standard once the disorder has been recognised.

The adverse outcomes, as categorised in the HAPO study, included increased rates of Caesarean delivery, increased foetal size, neonatal hypoglycaemia, and foetal hyperinsulinism. Each rose in a continuum related to increases of maternal fasting glucose level, and one hour, and two hour, levels after a 75g oral glucose load.

Two studies have been reported where a double blind methodology was used to decide whether treatment of gestational diabetes reduced perinatal complications: the ACHOIS study from 2005 and the Maternal-Foetal Medicine Units Network Trial from 2009. “A meta-analysis of these two studies showed that there was a significant reduction in pre-eclampsia with

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treatment, but neither an increase nor a decrease in Caesarean delivery rates,” says Fraser.

Birthweight was significantly reduced, as was the proportion of large for gestational age infants, and the incidence of shoulder dystocia (where the shoulders of the infant obstruct delivery of the infant’s body after successful delivery of the head). Treatment did not affect the incidence of neonatal hypoglycaemia.

The cost effectiveness of screening and treatment of GD has been addressed recently in a paper by Round and colleagues in Diabetologia (The journal of the European Association for the Study of Diabetes). Based on the two treatment RCTs, these trials assessed cost / benefit on the basis of the likelihood of a diagnosis of GDM in the individual. Where the risk was < 1% no screening or treatment strategy was cost effective. Where the risk was 1% - 4.2% a two-stage screening programme

UN summit faces up to global diabetes epidemic

N

EW DIABETES ATLAS figures released by the International Diabetes Federation (IDF) confirm that the diabetes epidemic continues to worsen. Data from global studies demonstrates that the number of people with diabetes in 2011 has reached a staggering 366 million, 4.6 million deaths are due to diabetes and healthcare spending on diabetes has reached 465 billion USD. The IDF launched the figures at the Lisbon meeting of EASD a week ahead of the UN Summit on Non-Communicable Diseases (NCDs) which has demonstrated that world leaders are finally facing up to the challenge posed by diabetes as well as cancer, heart and lung diseases.

As only the second UN Summit in history to deal with a health-related issue the global diabetes community is expecting international political leaders to sign-up to commitments, concrete actions and measurable targets to tackle NCD as they did at the ground-breaking High-Level Meeting on HIV/AIDS in 2001.

A key commitment demanded by leading diabetes experts meeting in Lisbon is for increased funding for research. In a joint commentary published in Diabetologia, IDF President Jean Claude Mbanya and EASD Vice-

President Andrew Boulton have warned: “Implementation of current knowledge will bring some improvements to NCD care and prevention, but further research is essential if we are to truly defeat these diseases. Indeed, without urgent research into improved care and prevention models, we stand little chance of meeting any long-term targets that arise from the Summit.”

Releasing the headline figures ahead of publication of the 5th edition of the Diabetes Atlas, the Heads of Government and State who met in New York on the 19th and 20th September should be in no doubt that the

diabetes is a massive challenge that they cannot afford to ignore any longer. The Atlas - based on the latest international data - demonstrates that diabetes remains increasing at an alarming rate.

Professor Mbanya said: “IDF’s latest Atlas data are proof indeed that diabetes is a massive challenge the world can no longer afford to ignore. In 2011 one person is dying from diabetes every seven seconds. The clock is ticking for the world’s leaders - we expect action from their meeting next week at the United Nations that will halt diabetes’ relentlessly upwards trajectory. The socioeconomic impact of not just diabetes, but all non-communicable diseases, is staggering,” Professor Boulton, Vice-President of EASD said.

“EASD fully supports the IDF and echoes the call of Professor Mbanya’s for increased funds for medical research.” Research into strengthening health systems should include developing and evaluating approaches for building local healthcare capacity, as well as integrating diabetes care and services with primary healthcare services, management of chronic infectious diseases and maternal and child health.

The message to world leaders is that investing in research now will result in savings in the future.

with fasting plasma glucose followed by oral glucose tolerance test was most likely to be cost -effective. Finally, with an individual risk greater than 4.2%, universal glucose tolerance testing was cost effective.

“Approaches to treatment should include diet, and supplementary insulin or oral hypoglycaemic agents (OHA) if diet alone fails to achieve acceptable glycaemic control,” says Fraser, who adds that a randomised trial of a low GI diet compared to a conventional high fibre diet by Moses et al in 2009, showed a halving of the requirement for supplementary insulin with the low GI diet.

A systematic review and meta-analysis of OHA versus insulin, in the management of gestational diabetes, has just been published in the American Journal of Obstetrics and Gynaecology. The various studies included OHA in the forms of glibenclamide or metformin. The review reported no difference between OHA and insulin in fasting glycaemic control, or post- prandial glycaemic control. No significant differences were seen in Caesarean section rates, neonatal birthweight, the proportion of large for gestational age babies, or the incidence of neonatal hypoglycaemia.

“This suggests that for many women

requiring supplementary hypoglycaemic therapy in addition to diet, OHA are a cheap and effective alternative. There is evidence from the MiG trial that metformin might be the drug of choice for those who are obese in association with their diagnosis of gestational diabetes,” concludes Fraser.

Across the UK and other developed countries, practice varies and many units still prefer insulin as the hypoglycaemic drug of first choice. Fraser suggests that should the costeffective treatments of diet and cheap oral agents be used, there could be substantial savings across the health system.

“IDF’s latest Atlas data are proof indeed that diabetes is a massive challenge the world can no longer afford to ignore.”

Professor Jean Claude Mbanya

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Urology Report

by Samuel Peters

Nearly half the world’s adults will experience LUTS by 2018 Study provides detailed projections for North and South America, Africa, Asia and Europe

N

EARLY HALF OF all adults over 20 will experience at least one lower urinary tract symptom by 2018 - an estimated 2.3 billion people and a worldwide increase of 18% in just one decade - according to research in the October issue of the urology journal BJUI. Other issues like incontinence will also increase, with South America, Asia and the developing regions of Africa particularly affected by the conditions, which are more common as people get older.

"Our study suggests that urinary and bladder symptoms are already highly prevalent worldwide and that these rates will increase significantly as the population ages" says lead author Dr. Debra E Irwin from the Department of Epidemiology at the University of North Carolina, USA. "These findings raise a number of important worldwide issues that will need to be tackled, as a matter of urgency, by clinicians and public health experts if we are to prevent, and manage, these conditions."

The research team calculated the numbers and prevalence of individuals aged 20 years plus affected by each condition in 2008, using data on gender and age from two key sources: Worldwide and regional population estimates from the US Census Bureau International Data Base The EPIC study, a large population-based, cross-sectional telephone survey of more than 19,000 men and women in five countries, led

by Dr. Irwin.

The data was then extrapolated to provide 2013 and 2018 estimates for lower urinary tract symptoms (LUTS), overactive bladder (OAB), urinary incontinence (UI) and LUTS suggestive of bladder outlet obstruction (LUTS/BOO), using the current symptom definitions from the International Continence Society.

"It is well known that people do not always seek medical attention for urinary problems, so basing our figures on studies using self-reported symptoms is an effective way of measuring worldwide prevalence" explains Dr. Irwin.

Key findings of the analysis include: The worldwide prevalence of LUTS will increase to just under 46% by 2018, affecting 47% of women and 45% of men.

Between 2008 and 2018 the number of people experiencing at least one LUTS will have grown by 18%, affecting an estimated 2.3 billion people, with the biggest increase in Africa (30%), followed by South America (20.5%), Asia (20%), North America (16%) and Europe (2.5%).

OAB will have increased by 20% between 2008 and 2018, affecting an estimated 546 million people, with the biggest increase in Africa (31%), followed by South America (22%), Asia (22%), North America (18%) and Europe (4%).

UI will have increased by 22% between 2008 and 2018, affecting an estimated 423 million people, with the biggest increase in Africa (31%), followed by South America (25%), Asia (24%), North America (18%) and Europe (5%).

LUTS/BOO will have increased by 18.5% between 2008 and 2018, affecting an estimated 1.1 billion people, with the biggest increase in Africa (30%), followed by South America (21%), Asia (20%) North America (16%) and Europe (3%).

"We believe that our study underlines the clear and urgent need to improve the awareness, prevention, diagnosis and management of these conditions" says Dr. Irwin, who worked with coauthors from the USA, UK and Sweden.

"International and national programmes that increase public awareness, educate clinicians and implement public health campaigns that tackle the social stigma of LUTS, will be a significant step towards reaching this objective.

"These public health programmes would need to be adapted by region, because countries often differ in their healthcare resources, treatment guidelines and social perceptions."

The full paper on the study, which was funded by Pfizer, provides detailed breakdowns of individuals with LUTS by gender and year. It also provides further statistics on the increases expected by 2013.

Reference: Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary. Irwin et al. BJUI. 108, pp1132 . (October 2011) doi:10.1111/j.1464410X.2010.09993,10498.x

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World Conference on Lung Cancer Reports from WCLC, Amsterdam by Dr. Sunil Upadhyay

The rivalry between cisplatin and carboplatin goes on: BTOG2 trial

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T THE RECENTLY held 14th World Conference on Lung Cancer in Amsterdam, on behalf of the investigators, the randomised Phase III clinical trial results of BTOG2 were presented by David Ferry. The primary end point of this long running trial was length of survival and the secondary end points were response rate, dose intensity of chemotherapy, ratio of cycles as inversus out- patients, incidence of toxic

R

DAY 1

DAY 8

Gemcitabine 1250mg/m2 + Cisplatin 80mg/m2

Gemcitabine 1250mg/m2

DAY 1

DAY 8

Gemcitabine 1250mg/m2 + Cisplatin 50mg/m2

Gemcitabine 1250mg/m2

DAY 1

DAY 8

Gemcitabine 1250mg/m2 + Carboplatin AUC6 (Wright)

Gemcitabine 1250mg/m2

episodes, cost and cost effectiveness.

A maximum of 4 cycles of the chemotherapy were given. There were 456 patients in the GC80, 454 in the GC50 and 453 in the GCb arms. The median age of the patients entered in this trial was 64 years. The other characteristics were well balanced including histology.

Approximately one third of the patients had adenocarcinoma, one third squamous cell and the remainder were others. Similarly, 32% of the patients had stage IIIB disease and 68% stage IV. The majority of the patients were PS 0 or 1. Only about two thirds of the patients in each arm completed 4 cycles of planned chemotherapy.

At a median follow-up of 22 months, the median OS was 9.5 months for GC80, 8.2

12

months for GC50 and 10.0 months for GCb (p=0.09). The one-year overall survival was 39% with GC80, 31% with GC50 and 39% with GCb (p=0.09). It was concluded that the use of the Wright equation to determine GFR and dose of carboplatin led to doses on average being 10% higher than if the Cockcroft-Gault formula had been used. In combination with gemcitabine, carboplatin AUC6 (Wright) is not inferior to the best performing cisplatin arm

(cisplatin 80mg/m²). There was a trend to inferior survival with cisplatin 50mg/m² compared to cisplatin 80mg/m2. Therefore, carboplatin AUC6 Wright can be used instead of cisplatin 80mg/m2 in combination with gemcitabine in advanced NSCLC safely without loss of efficacy.

The BTOG2 results confirm that carboplatin is not inferior to cisplatin 80mg/m² provided the optimum dose is used. It also provides the evidence that cisplatin 50mg/m² is inferior to cisplatin 80mg/m². Therefore, carboplatin can be used instead of cisplatin 80mg/m² in combination with gemcitabine without any risk of loss of efficacy.

The issue of the equivalence between carboplatin and cisplatin in the treatment of

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advanced NSCLC was also looked into through the CISCA meta-analysis and the results were presented by Andrea Ardizzoni at ASCO 2006 (abstract no 7011). This meta-analysis of nine trials (cisplatin 1489 and carboplatin 1479 patients) found that cisplatin-based chemotherapy was superior to carboplatinbased chemotherapy in terms of response rate, though increased response rate did not translate into an OS benefit (7% less risk of death; HR=1.07, p=0.101). However, in CISCA analysis, only 3 were large trials and 4 were relatively small trials.

Similarly, the meta-analysis by Hotta et al 1 found that cisplatin-based chemotherapy produced a higher response rate, more frequent nausea & vomiting but no survival advantage (HR=1.05, p=0.515). However, the London Lung Cancer Group Phase III trial comparing carboplatin (AUC5) plus gemcitabine versus mitomycin, ifosfamide and cisplatin 50mg/m² (MIC) was reported to show a median survival of 10 months with GCb compared to 7.6 months with MIC, a difference of 2.4 months and one-year survival of 40% with GCb compared to 30% with MIC similar to BTOG2 results. Professor Ming Lee from UCL in his comments concluded that cisplatin dosage is important in NSCLC and inferior results observed with second-generation chemotherapy regimens is probably due to the low dosage of cisplatin. The BTOG2 trial results provide reassurance to treat NSCLC patients with either platinum compound without loss of efficacy. He observed that this study should be the final study on cisplatin vs carboplatin rivalry and platinum with either gemcitabine, pemetrexed or taxane doublet should remain the current standard chemotherapy for the management of advanced non-small cell lung cancer. (Abstract 001:003).

Reference: 1. Hotta K, Matsuo K, Ueoka H, Hiura K, Tabata M, Tanimoto M. JCO 2004; 22: 3852-3859

Emerging immunotherapies in the management of lung cancer

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DVANCED NON-SMALL cell carcinoma of the lung represents one of the major unmet needs for an effective and prolonged survival outcome.

The majority of these patients frequently present to the multi-disciplinary team at an advanced stage with little chance of radical management options and extremely poor prognosis. Treatment with currently available chemotherapy, molecular agents and radiotherapy have been found to result in median overall survival of 15-18 months in the majority of the studies for stage IIIB and IV disease. Co-morbidities and toxicities from these therapies are the other concerns, particularly in patients with poor performance status and the elderly biological age.

Use of immunotherapeutic agents to stimulate or restore the ability of the immune system to fight cancer by inducing, enhancing or suppressing an immune response has been an area of interest for decades but with limited success. Cancer immunotherapy agents target the immune activity against a disease specific antigen either by increasing the immune cell recognition of the target or by reducing the disease-related immune suppression. These agents have low toxicity hence are suitable for use in a wide variety of patients. The uses of preventive cancer vaccines targeting viruses know to cause cervical and liver cancers are examples of real breakthroughs. Unlike preventive cancer vaccines, therapeutic cancer vaccines are designed to be used after the development of the disease. These agents stimulate the immune system to be able to recognise cancer cells by exposure to tumour specific antigens and then target the cancer cells, stop their growth, prevent metastases and eventual relapse.

A therapeutic vaccine can be used as adjuvant therapy following primary radical treatment with surgery, radiotherapy with or without chemotherapy to reduce the relapse and improve cure in early or locally advanced NSCLC patients.

The therapeutic vaccine STIMUVAX stimulates the body’s immune system to reject cancer cells

and prevent tumour growth, metastasis or recurrence. Stimuvax is based primarily around the mucin-1 (MUC-1) glycoprotein, a tumour antigen discovered by Cancer Research UK and found on almost all cancer cells including NSCLC. MUC-1 is involved in the formation of mucin which keeps the epithelial cell surface moist and may also act as an immunosuppression substance. Abnormal glycosolated MUC-1 has been found to be over expressed on many tumour cells compared to normal epithelial tissue.

A vaccine based on abnormally glycosolated MUC-1 like Stimuvax (BLP25 liposomal vaccine) has been found to show encouraging activity in Phase II trials for stage IIIB lung cancer. Therefore, a large Phase III trial called START (Stimulated Targeted Antigenic Response to NSCLC) is being set up to recruit 1300 patients with stage III disease from around the world. Data from a Japanese study looking at the efficacy and feasibility of MUC-1-targeting dendritic cell-based vaccine immunotherapy in 43 patients yielded an overall disease control rate of 61.5% with minimal toxicities. (Abstract MO21.09).

RCAS 1 (Receptor binding cancer antigen expressed on SiSO cells) is another membrane protein that is expressed in different types of cancers. It halts the cell cycle and induces apoptosis of the immune system cells within the tumour micro-environment. Therefore, it is possible that this molecule is involved in the mechanism of the tumour cell escape from the immune system surveillance. A study presented at the 14th WCLC confirmed that there is an overexpression of RCAS 1 protein mainly in grade 3 lung cancers and that there is positive correlation between RCAS 1 and ki-67 expression which means that when the ki-67 increases, the expression of RCAS 1 is higher. Therefore, RCAS 1 could be considered as a marker of the tumours aggressiveness (Abstract P2.232 late breaking Abstract suppl).

Ipilimumab, a fully human monoclonal antibody which augments T cell activation by selectively inhibiting T-lymphocyte antigen-4 is

one of the few immunotherapies that has shown positive results in treating advanced lung cancers in combination with paclitaxel/carboplatin (PC). The Phase II trial results presented by Thomas Lynch at the 2010 Chicago Multidisciplinary Symposium in Thoracic Oncology showed superior PFS when ipilimumab was combined with PC compared to PC alone. Thomas Lynch presented the updated results of the analysis by baseline histology from this trial at WCLC 2011.

The primary end point of this study was immune-related irPFS. Squamous cell carcinoma tumours were found to benefit most with the phased schedule. The AE profile of Ipilimumab was found to be identical in both schedules irrespective of histology. Despite the small sample size, the results are encouraging and warrant further investigation in larger Phase III trials. (Abstract MO21.06).

Active immunisation against MAGE-A3 tumour antigen, commonly expressed in many cancers, is also being investigated. MAGE-A3 tumour-specific antigens are appealing because they have little crossover with normal tissue antigens. Therefore, MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) has been developed and following encouraging Phase II trial outcomes, MAGE-A3 ASCI is currently being investigated in a global Phase III, randomised (2:1) trial called MAGRIT as adjuvant therapy after surgery in NSCLC. The tumour and patient characteristics associated with MAGE-A3 expression results were presented by Joo-Hang Kim from South Korea.

The overall rate of MAGE-A3 expression was found to be 33.4%. There were major differences between MAGE-A3 expression in squamous (47.5%) and non-squamous (25.7%) tumours. Other clinical variables had little impact on predicting MAGE-A3 expression. However, among non-squamous tumours, non-Asian race, male sex, and larger tumour size were significant predictors for MAGE-A3 expression.

(Abstract MO21.08).

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World Conference on Lung Cancer Reports from WCLC, Amsterdam by Dr. Sunil Upadhyay

Defining the unmet needs in NSCLC

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HE WAY WE have defined cancer has not changed over centuries.

Most of the lung cancers are associated with smoking. There is plenty of evidence to suggest that lung cancers in never smokers are a distinct pathology in terms of carcinogenesis, clinical characteristics, anatomical distribution, biology and prognosis.

With rapid scientific progress and availability of modern technologies, lung cancer, from being a single disease has become multiple diseases.

Based on the histology, it used to be broadly divided into two main groups i. e. squamous cell carcinoma and non-squamous cell carcinoma.

This was simply brought about by emerging differences in their systemic treatment selection by oncologists. The most commonly used marker for the squamous cell carcinoma is p63 and CK 5/6 though desmocollin-3 (DSC3) is probably the most specific marker. Similarly, TTF1, CK7 are frequently used for adenocarcinoma though Napsin A and mucin stains are most specific but lack sensitivity. The histopathological distinction was essential for judicious use of tissue and chemotherapy regimen selection. However, over the last decade, the canvas has changed. This has been brought forward mainly following the most exciting discovery of molecular profiling of cancer. Who could have predicted that lung cancer would be the front runner in the race for gene profiling and molecular targeted therapy even as late as 15 years ago? Discovery of EGFR mutation led to the development and successful treatment of TKI therapy.

Lung cancer is known to harbour multiple genetic mutations particularly adenocarcinoma like KRAS, EGFR, BRAF, ALK, c-Met, HER2, PI3KCA and many others. Similarly, adenocarcinoma in never smokers, particularly Asian females is more frequently associated with EGFR, EML4-ALK and less frequently with KRAS and c-MET mutation. Though KRAS remains the most difficult mutation to understand, most of the other genes are already being targeted with promising outcome. Many of these agents are already in routine clinical use and others are showing promising results in Phase II and III trials. The role

14

of gefitinib as first-line systemic Potential molecular targets treatment in exon 19 & 21 EGFR mutation positive Unknown tumours was confirmed in the KRAS EGFR iPASS trial. E4599 trial data HER2 showed unprecedented extra MEK1 overall survival benefit of 3.9 BRAF months in bevacizumab ALK fusion treated group (HR=0.69).

PIK3CA The latest excitement has been ROS fusion the results of crizotinib, an PDGFR ALK-MET kinase inhibitor in ALK positive tumours. profiling has to be based on small cytology and The genetics of squamous cell carcinoma small biopsy samples. Frequently these small have not remained untouched. Some of the samples contain only a few undifferentiated significant genetic alterations already detected cells and so tumour subtype prediction like c-MET, p53 mutation, FGFR1 and DDR2 are becomes difficult. Therefore, EGFR mutation potential therapeutic targets. Peter testing in plasma has been attempted and the Hammerman presented a detailed genomic sensitivity reported has been variable and analysis of squamous cell carcinoma of lung proper validation of these techniques is tumours (n=118) at the Presidential Symposium essential. We need to know the number, group (PRS.1). Several other genes likely to be and “drivers” of genes critical for making the important in the pathogenesis and treatment decision. How to account for the management of lung cancer are CMYC, differences between prognostic and predictive PDGFRA, EGFR, HER2, CCNV1 and PTEN. markers? The precise target for some of the Agents targeting the FGFR, PI3KCA and DDR family are already undergoing clinical Table: Prevalence of genetic mutation testing. The role of Squamous cell carcinoma Adenocarcinoma thymidylate synthase KRAS mutation 5% 10-30% BRAF mutation 3% 2% (TS), ERCC1 and RRM1 EGFR for selection of Mutation TK 2-5% 10-40% platinum or nonAmplification 30% 15% Mutation variant III 5% Rare platinum doublets is HER2 getting stronger.

Mutation TK Rare 2-4% Therefore, clinical Amplification 2% 6% and histological ALK (fusion) Rare 7% MET characteristics alone Mutation 5% 5% should not be used for Amplification <10% <10% treatment selection.

P53 mutation 60-70% 50-70% LKB1 mutation 10-20% 3-40% One must define the PIK3CA tumours based on Mutation 2% 2% genetic mutation, Amplification 33% 6% deletion, amplification Jean-Charles Soria WCLC 2011 and loss of targeted agents like bevacizumab and heterozygosity. This welcoming knowledge has cetuximab remains hazy. Better understanding pushed us away from histology to molecular is essential to be able to translate these biology and personalised therapy. advances from clinical trials into daily practice.

Unfortunately, this histological and molecular

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

LET’S THINK

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

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Back pain

by Bruce Sylvester

Chronic, non-cancer pain treatments are sub-optimal in most patients

T

REATMENTS USED to treat chronic, non-cancer pain do not alleviate such pain or restore normal functioning in the majority of patients, researchers report. The findings were published in The Lancet on June 23.

Chronic pain is estimated to affect 20% of people worldwide and is very expensive to health systems.

In the USA alone, spending is over US$210 billion annually.

Lead investigator Dennis Turk, PhD, Professor of Anesthesiology and Pain Research Director, Fibromyalgia Research Center at the University of Washington in Seattle and colleagues reviewed the evidence for the effectiveness of the most commonly used interventions to treat chronic pain which have been used over the past decade.

They found that, in spite of important

advances in knowledge of the mechanisms underlying pain and a growing range of treatment options, overall effectiveness of treatment remains inconsistent and poor. "Of all treatment modalities reviewed [drugs, surgery, interventional, behavioural, rehabilitation, and alternative], the best evidence for pain reduction averages roughly 30% in about half of treated patients, and these pain reductions do not always occur with concurrent improvement in function," they said.

Chronic pain is estimated to affect 20% of people worldwide and is very expensive to health systems. In the USA alone, spending is over US$210 billion annually.

The investigators note that, since current monotherapy for chronic pain offers only modest improvements in pain and physical and emotional functioning, research should focus on the effectiveness of combining various treatments (combinations of several drugs, drugs with somatic treatments, and pharmacological and psychological treatments).

They also note that few clinical trials have assessed combinations of therapies, and little evidence exists in such trials for the beneficial

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

16

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

effect of any particular combination.

They recommend the development of a holistic approach to chonic pain treatment, including a measure of physical and emotional functioning, patient ratings of improvements and adverse events, rather than only an assessment of pain severity.

They conclude, "A great need exists for research that goes beyond asking the questions of whether a particular treatment is effective, to addressing what treatment is effective, for which patients, on what outcomes, under what circumstances, and at what cost….These results suggest that none of the most commonly prescribed treatment regimens are, by themselves, sufficient to eliminate pain and to have a major effect on physical and emotional function in most patients with chronic pain…There is a crucial need for assessment of combination treatments, identification of treatment response, and the assessment of the benefit of matching of treatments to patient characteristics."

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PALEXIA SR® and PALEXIA® Prescribing Information Refer to the Summary of Product Characteristics (SmPCs) before prescribing. Presentation: Palexia SR: 50 mg (white), 100 mg (pale yellow), 150 mg (pale pink), 200 mg (pale orange) and 250 mg (brownish red) prolonged-release tablets contain 50 mg, 100 mg, 150 mg, 200 mg and 250 mg of tapentadol (as hydrochloride) respectively. Palexia: 50 mg (white) and 75 mg (pale yellow) film-coated tablets contain 50 mg and 75 mg of tapentadol (as hydrochloride) respectively. Indication:Palexia SR is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. Palexia is indicated for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics. Dosage and method of administration: Individualise according to severity of pain, the previous treatment experience and the ability to monitor the patient. Swallowed whole with sufficient liquid, with or without food.

Palexia SR should not be divided or chewed. Palexia SR dosage: Initial dose 50 mg twice a day. Switching from other opioids may require higher initial doses. Titrate in increments of 50 mg twice a day every 3 days for adequate pain control. Total daily doses greater than 500 mg not recommended. Palexia dosage: Initial dose 50 mg every 4 to 6 hours. On the first day of dosing, an additional dose may be taken 1 hour after the initial dose, if no pain control. The first day’s dose should not exceed 700 mg. Maximum maintenance daily dose of up to 600 mg. Discontinuation of treatment: Taper dose gradually to prevent withdrawal symptoms. Renal/hepatic impairment: Not recommended in severe patients. Caution and dose adjustments with moderate hepatic impairment. Elderly: May need dose adjustments.

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

Consider dose reduction with respiratory or CNS depressant agents.

In isolated cases, serotonin syndrome has been reported with Palexia SR/Palexia in combination with serotoninergic medicinal

products (e.g. serotonin re-uptake inhibitors). Care should be taken with mixed mu-opioid agonist/antagonists or partial mu-opioid agonists due to risk of reducing the analgesic effect. Use with strong inhibitors of uridine diphosphate transferase isoenzymes (involved in glucuronidation) may increase systemic exposure of Palexia SR/ Palexia. Risk of decreased efficacy or adverse events if used with strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John’s Wort). Pregnancy and lactation: Do not use. Driving and using machines: May have major effect on ability to drive and use machines, especially at the beginning or change in treatment, in connection with alcohol or tranquilisers. Undesirable effects: Very common (≥1/10): dizziness, somnolence, headache, nausea.

Palexia SR only: constipation. Palexia only: vomiting. Common (≥1/100, <1/10): decreased appetite, anxiety, sleep disorder, tremor, flushing, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change. Palexia SR only: depressed mood, nervousness, restlessness, disturbance in attention, involuntary muscle contractions, dyspnoea, vomiting, mucosal dryness, oedema. Palexia only: confusional state, hallucinations, dry mouth, muscle spasms, constipation, abnormal dreams. Other important undesirable effects: Palexia SR only: drug hypersensitivity (uncommon ≥1/1000, <1/100), respiratory depression (rare ≥1/10,000, <1/1000); Palexia only: respiratory depression (uncommon ≥1/1000, <1/100), hypersensitivity (rare ≥1/10,000, <1/1000). No evidence of increased risk of suicidal ideation or suicide with Palexia SR/Palexia. Consult the SmPCs for full details. Overdose: Seek specialist treatment (see SmPCs). Legal classification: POM, CD (Schedule II). Marketing Authorisation

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

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Grünenthal Ltd (telephone 0870 351 8960).

References 1. Palexia SR, Summary of Product Characteristics.

February 2011

P11 0078aj Date of preparation: November 2011

European Multidisciplinary Cancer Congress Reports from the EMCC, Stockholm by Peter Mas-Mollinedo

Identification and management of breakthrough cancer pain remains a challenge

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EUROPEAN ONCOLOGY nurse survey calls for greater clinical consensus on diagnosis and treatment of breakthrough cancer pain; new guidelines are on their way.

The results from The European Survey of Oncology Nurse Breakthrough Cancer Pain Practices were presented for the first time at The European Multidisciplinary Cancer Congress in Stockholm. The survey was performed for the Breakthrough Cancer Pain Initiative, a European Oncology Nursing Society (EONS) working group.

Lack of pain assessment tool leads to sub-optimal treatment The survey which collected 1,164 completed responses among nurses from 12 European countries is the first European survey to look at oncology nurse perception of breakthrough cancer pain and its management.

Breakthrough cancer pain is short, often debilitating, episodes of intense pain that are experienced by many cancer patients, despite having their chronic background pain controlled with medication.

The survey shows that distinguishing a patient's breakthrough cancer pain as a separate symptom from their chronic background pain represents an area of challenge for nurses practicing in a cancer setting. In fact, a key finding of the survey was an unmet training need for the management of breakthrough cancer pain among nurses since the majority (57%) reported that they had not received training on breakthrough cancer pain management. The proportion of nurses receiving training in breakthrough cancer pain management varied significantly between countries with 72% of Finnish nurses receiving training whilst only 6% of Greek nurses receiving training.

The survey results clearly show that there is an enormous opportunity to improve the pain outcomes of cancer patients via education. As

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an example, nearly half of the respondents reported that they do not utilise a pain assessment tool to help them describe this type of pain with variation between countries. Taken together, the respondent's answers support that breakthrough cancer pain is under-recognised, may be treated inappropriately and impacts on patients’ daily lives. The identified education gap of breakthrough cancer pain and its management, combined with no formal consensus about optimal pain management among oncology nurses should be addressed, says Professor Tone Rustøen, Division of Emergencies and Critical Care, Oslo University Hospital, and member of the advisory group to the Breakthrough Cancer Pain Initiative.

When presenting the survey results, Tone Rustøen noted that the management of breakthrough cancer pain should be implemented as an integral part of nurses’ cancer pain treatment training in order to improve patient pain outcomes and well-being.

Need for more knowledge on medication options The survey revealed a number of areas for additional education and guidance to nurses that can result in modified practice patterns that may improve breakthrough cancer pain management. An important area is the understanding of medication options. In the survey, the majority (57%) of the nurses reported that most of their patients receive medication for the treatment of breakthrough cancer pain.

However, the suitability of these medications may be called into question in their healthcare setting. Nearly 40% of the nurses say they are not aware that medication specifically designed for breakthrough cancer pain exists.

Breakthrough cancer pain is a distinct problem and requires specific interventions, including rescue medications that have an appropriately fast onset of action.

Unfortunately, many patients are being treated with medication that is better suited for

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

management of persistent pain, and these patients are, therefore, not receiving the most appropriate treatment for their breakthrough cancer pain, says Dr. Andrew Davies, Department of Palliative Care, St. Luke's Cancer Centre, UK, and also a member of the advisory group to the Breakthrough Cancer Pain Initiative.

Oncology nurses request more knowledge Also, most nurses (78%) report that breakthrough cancer pain significantly impacts patients' lives and almost all (81%) have found it difficult to control their patients' pain during the past month. This is further reflected in 36% of the nurses not feeling confident in advising patients about breakthrough cancer pain management and in 77% reporting a need for more information on breakthrough cancer pain.

New guidelines on their way A starting point to address unmet education need is consensus and guidance to nurses on the management of breakthrough cancer pain.

In the absence of nurse-specific guidelines, the European Oncology Nursing Society (EONS) will develop guidelines which describe and explain breakthrough cancer pain as an independent phenomenon with its own clinical symptoms, says Executive Director Clair Watts, European Oncology Nursing Society and continues: The objective of the guidelines is to provide guidance on assessment, identification and treatment of breakthrough cancer pain, which will serve as a platform to implement nursespecific training programmes.

The EONS Breakthrough Cancer Pain guidelines were presented in conjunction with the survey at The European Multidisciplinary Cancer Congress.

To learn more about the Breakthrough Cancer Pain Initiative and the European Survey of Oncology Nurse Breakthrough Cancer Pain Practices, please visit: www.cancernurse.eu/btcp

y an th ths pir ss on ex Le m ent 12 pat til un

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

candesartan cilexetil For all the right reasons

Abbreviated Prescribing Information - Amias® (candesartan cilexetil) (Refer to Summary of Product Characteristics before prescribing) Presentation: Tablets containing 2mg, 4mg, 8mg, 16mg or 32mg candesartan cilexetil. Indication: Essential Hypertension in adults; Treatment of adult patients with heart failure and impaired left ventricular systolic function (LVEF ≤ 40%) as add-on therapy to ACE-inhibitors or when ACE-inhibitors are not tolerated. Dosage: In hypertension: Starting and usual maintenance dose is 8mg od with or without food. Most of the antihypertensive effect is attained within 4 weeks. In some patients, whose blood pressure is not adequately controlled, the dose may be increased to 16mg od and to a maximum of 32mg od. No dose adjustment is necessary in the elderly. A starting dose of 4mg is recommended for patients with renal impairment (including haemodialysis), with mild to moderate hepatic impairment and those at risk of hypotension due to intravascular volume depletion. In heart failure: Usual starting dose is 4mg od with or without food. Up-titration to the target dose of 32mg od or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks. No dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion, renal impairment or mild to moderate hepatic impairment.

Amias can be administered with other heart failure treatment including ACE-inhibitors, beta-blockers, diuretics and digitalis or a combination of these. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and Amias is not recommended and should be considered only after careful evaluation of the potential benefits and risks.

Safety and efficacy of Amias not established in children. Contraindications: Hypersensitivity to any component of Amias. Second and third trimesters of pregnancy. Severe hepatic impairment and/or

cholestasis. Warnings and Precautions: Monitoring of serum potassium and creatinine levels is recommended during dose titration of Amias in patients with heart failure and regularly in patients taking concomitant ACE-inhibitors and potassium sparing diuretics such as spironolactone. Periodic assessments of renal function is also recommended especially in elderly heart failure patients ≥ 75 years and in heart failure patients with impaired renal function. Hypotension may occur during treatment with Amias in heart failure patients. Risk of increased blood urea and serum creatinine in patients with renal artery stenosis. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment. Amias should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted. Possible hypotension during anaesthesia and surgery. Not recommended in patients with primary hyperaldosteronism. As with other vasodilators, use with caution in patients with aortic and/or mitral valve stenosis or obstructive hypertrophic cardiomyopathy. Amias should not be initiated during pregnancy. When pregnancy is confirmed, treatment with Amias should be stopped immediately, and, if appropriate, alternative therapy commenced. Amias is not recommended during breastfeeding.

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

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

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

Please refer to the summary of product characteristics for details on the full side-effect profile and drug interactions of Amias. Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Takeda UK Ltd. References: 1. Meredith PA et al. J Hum Hypertens. 2010; 24(8): 525-31.

2. Kjeldsen SE et al. J Hum Hypertens 2010; 24(4): 263-273. 3. EklindCervenka M et al. JAMA 2011; 305(2): 175-82. 4. Young JB et al.

Circulation 2004; 110: 2618-2626. 5. Takeda UK Ltd. Amias (candesartan cilexetil) Summary of Product Characteristics. www.medicines.org.uk. † Reduced risk of cardiovascular disease, morbidity, mortality and elective coronary revascularisation. ‡ Amias is the only ARB licensed for heart failure that can be prescribed as an alternative in patients intolerant to ACE-inhibitors, or in addition to an ACE-inhibitor with/without a betablocker in patients with LVEF ≤40%.

Code: TA110579d Date of preparation: May 2011

www.heartzone.co.uk

Cardiology Reports

by Bruce Sylvester

Stroke prevention clinics reduce one-year mortality rates by over 25% Two Canadian studies have emphasised the importance of stroke prevention clinics and cardiac rehabillitation programmes

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ECENTLY PUBLISHED research has shown just how important it is for patients to be referred to a stroke prevention clinic following either a mild stroke or a transient ischaemic attack (TIA). The study, published in the journal Stroke in November, showed a 26% reduction in one-year mortality rates among those referred to a stroke prevention clinic.

The risk of stroke after a TIA may be as high as 20% in the first three months. Half of the strokes occur in the first 24 to 48 hours after a TIA. Organised inpatient care has been shown to decrease morbidity and mortality but little research has been done on the benefits of organised outpatient stroke prevention clinics.

These clinics facilitate early assessment, diagnosis and treatment of patients with a

recent TIA or non-disabling stroke.

Using data from the Registry of the Canadian Stroke Network, the researchers compared more than 16,000 patients with ischaemic stroke or TIA seen in the emergency department or admitted to hospital in Ontario between July 1, 2003 and March 31, 2008.

"Organised stroke care works," says Dr. Hachinski, a Professor in the Department of Clinical Neurological Sciences at Western's Schulich School of Medicine & Dentistry, and a Scientist with the Lawson Health Research Institute. "It doesn't really matter about the size, location and hours of these clinics. Patients benefit because you have interested people with some expertise, following best practice standards and gaining experience from doing things repeatedly."

"This study provides important evidence that referral to a SPC reduces mortality. The basic underlying principle of our study is that organised care, even with staggered models, makes a positive difference at all levels," adds Fiona Webster, first author and Education Scientist/Assistant Professor in the Department of Family and Community Medicine at the University of Toronto.

Funding for the study was provided by the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long-Term Care and the Canadian Stroke Network.

Contact: Kathy Wallis For further information on the study please contact kwallis3@uwo.ca

Cardiac rehabilitation programmes benefit patients after mini or mild stroke

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ARDIAC REHABILITATION, traditionally used after heart attack to prevent future heart problems, seems similarly effective for people who have a transient ischaemic attack (TIA) or mild stroke, according to new research published in Stroke: Journal of the American Heart Association.

TIA, also called mini-stroke, is a warning sign. While causing little or no permanent injury to the brain, patients are at high risk for subsequent, often debilitating strokes. In the study, researchers defined a mild stroke as one that didn't cause significant disability.

"Many of the risk factors that we worry about after a heart attack - high cholesterol,

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with heart conditions and wondered whether it was feasible, effective and safe for patients after TIA or mild stroke."

Suskin and colleagues assessed cardiac risk factors in 100 patients who had experienced a TIA or mild stroke in the previous year. Patients participated in an "Many of the risk factors that we outpatient cardiac rehab programme worry about after a heart attack ... for approximately 7½ months and then also concern us after a TIA." were re-assessed for risk factors.

Researchers assessed the effectiveness Dr. Neville Suskin of the rehab process, which included exercise; drug management; nutrition education; smoking cessation; and addressing psychological issues such as stress, anxiety, or depression. Eighty patients investigator of the study. "We know that cardiac completed the rehab process. rehab addresses these risk factors in patients smoking, low exercise capacity and high blood pressure - also concern us after a TIA," said Neville Suskin, M.B.Ch.B., M.Sc., senior

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

Overweight or obese children have a tripled risk of high blood pressure

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HILDREN WHO ARE overweight or obese children have a threefold increased risk of developing high blood pressure compared with children of normal weight, researchers reported on Oct. 3 in the online edition of Hypertension.

"Higher blood pressure in childhood sets the stage for high blood pressure in adulthood," said lead investigator Wanzhu Tu, Ph.D., professor of biostatistics at Indiana University School of Medicine in Indianapolis. "Targeted interventions are needed for these children.

Even small decreases in BMI could yield major health benefits."

Over 1,100 healthy Indiana school children were followed for nearly five years. When body mass index (BMI) reached or exceeded the 85th percentile for the age and gender of the child (defined as “overweight), the risk of high blood pressure nearly tripled. Obesity was defined as a BMI percentile higher than 95th.

Also, 14% of overweight or obese subjects became pre-hypertensive or hypertensive,

compared to 5% of normal weight subjects.

The findings were consistent across age, gender and race.

The average age at time of study enrollment was 10.2 years. The researchers assessed each subject approximately eight times during the study. All of the subjects were healthy, and none took medication affecting blood pressure.

The researcher also reported that leptin, a protein hormone which is involved in body weight regulation and metabolism, was positively associated with increased blood pressure in overweight and obese subjects.

"Previous studies overestimated the effect of BMI on blood pressure in children of normal weight and

underestimated the effect of high BMI on overweight and obese children. Now we see the significantly greater risk of high blood pressure in overweight and obese children. But we don't yet know what makes blood pressure go up when there is an increase in the BMI percentile and the mechanisms involved in that process," Dr. Tu added.

"Overall, following the cardiac rehab intervention, the TIA and mild stroke patients improved significantly in their risk profile," said Suskin who is also a scientist at Lawson Health Research Institute in London, Ontario, Canada.

Patients' peak exercise capacity improved by an average of about 31% by the end of cardiac rehabilitation.

per square meter (kg/m2) and body weight decreased by 3.2 pounds.

Systolic blood pressure dropped by three millimeters of mercury (mmHg) and diastolic declined by 2mmHg (these represent promising but statistically non-significant changes in blood pressure).

A significant number of patients became non-smokers.

The researchers also reported that 11 more patients, who at programme entry were at moderate or high risk of dying during the next year, after cardiac rehab completion were recategorised to lowest risk of death.

"While a TIA or mild stroke may seem small, in reality these events are crucial warning signs of possible catastrophic stroke or heart attack," said Peter L. Prior, Ph.D., C.Psych., lead author of the study, clinical psychologist in the

London Health Sciences Center Cardiac Rehabilitation & Secondary Prevention Programme and adjunct clinical professor in the Department of Psychology at the University of Western Ontario. "Our study is novel because it shows that cardiac rehabilitation, involving structured programmes in exercise, nutrition, smoking cessation and psychological services, is a feasible, potentially effective way for TIA or mild stroke patients to reduce their risk of strokes or heart attacks."

To confirm the results, the researchers are conducting a randomised controlled study, comparing the results of cardiac rehab in TIA or mild stroke patients, to a control group who receive only usual care.

Other findings include: Total cholesterol decreased by an average 11.6 milligrams per decilitre (mg/dl).

Triglycerides decreased by 23.9mg/dl.

Low density lipoprotein decreased by 9.3mg/dl, while high density lipoprotein increased by 2.3mg/dl (changes which were promising but statistically non-significant).

Waist circumference decreased by one inch.

Body mass index decreased by 0.5 kilograms

The Ontario Ministry of Health and Long-term Care, through the Stroke Strategy of Ontario, funded the study.

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

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European Society of Cardiology Reporting from the ESC Congress, Paris by Peter Mas-Mollinedo

Considerably lower risk of stent thrombosis and restenosis in 'new generation' drug-eluting stents A report from the nationwide complete Swedish Coronary Angiography and Angioplasty Registry (SCAAR)

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ESULTS FROM the SCAAR study, presented at the ESC Congress 2011, showed that Percutaneous Coronary Intervention (PCI) with "new generation" Drug-Eluting Stents (DES), was associated with a 38% lower risk of clinically meaningful restenosis and a 50% lower risk of stent thrombosis compared to old generation DES. Although many trials and studies support the overall early and mid-term safety and efficacy of first-generation drug-eluting stents, there has been concern on their long-term safety, especially regarding the potential risk of late stent thrombosis as well as late restenosis.

New drug-eluting stents (n-DES) have been developed with the purpose of overcoming the current limitations of the older generation drugeluting stents (o-DES).

The purpose of this study was to evaluate the long-term outcome in all patients who underwent stent implantation with bare metal stents (BMS), o-DES and n-DES in Sweden, using a national registry with complete consecutive enrolment, the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).

The SCAAR holds data on consecutive patients from 29 centres that perform coronary angiography and PCI in Sweden. The registry is sponsored by the Swedish Health Authorities and is independent of commercial funding. The technology is developed and administered by the Uppsala Clinical Research Center. Since 2001, SCAAR has been Internetbased, with recording of data online through an Internet interface in the catheterisation laboratory; data are transferred in an

22

encrypted format to a central server at the Uppsala Clinical Research Centre.

All consecutive patients undergoing coronary angiography or PCI are included. Information with respect to restenosis and stent thrombosis has been registered for patients undergoing any subsequent coronary angiography for a clinical reason since the beginning of 2004.

The study included 94,384 stent implantations in Sweden (BMS, n=64,631; o-DES, n=19,202; n-DES, n=10,551), from November 2006 to October 2010. Follow-up was performed up to two years post-intervention.

The performance up to two years of different types of n-DES was evaluated in an unselected large real-world populationincluding patients with myocardial infarction, three-vessel and/or left main disease, bifurcation lesions, graft disease, restenotic lesions and chronic total occlusions.

The main findings of this study are that PCI with n-DES was associated with a 38% lower risk of clinically meaningful restenosis and a

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

50% lower risk of stent thrombosis compared to o-DES. Further studies are needed in order to attempt to discriminate whether one of the three components of the n-DES - the polymer, the stent alloy, the eluting-drug - is mainly involved in decreasing the incidence of stent thrombosis and restenosis.

Improved stent designs with thinner struts, more biocompatible polymers may have an important impact on drug elution profiles, endothelial coverage, and functional recovery.

In conclusion, we showed that patients treated with PCI with n-DES have a considerably lower risk of restenosis and stent thrombosis at two years compared to o-DES in a large real world population.

These findings can be useful for the management of patients with high risk profile that could benefit more from these new devices.

Press release

.PRESS RELEASE...PRESS RELEASE...PRESS RELEASE.

IMI winners of 2011 eHealthcare Leadership Awards Recognised at Healthcare Internet Conference in Orlando

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MI INTERNATIONAL MEDICAL INFORMATION (the sister company to ICR-UK publishers of Evidentia), receives award for Best Integrated Marketing Campaign at the 2011 eHealthcare Leadership Awards. IMI, one of more than 300 healthcare organisations representing a broad industry spectrum, received recognition for their outstanding website and digital communications at a special presentation in Orlando on November 9 during the Fifteenth Annual Healthcare Internet Conference. Winners of the 2011 eHealthcare Leadership Awards were selected from nearly 1,200 entries. A total of 114 experts familiar with healthcare and the Internet judged the entries.

Managing Director, Peter Mas-Mollinedo commented, “We are delighted to receive this award as it recognises our passion for an integrated approach to digital marketing in the healthcare arena. It shows that multi-channel communications can be really effective when the content is good. It is a great result for our team who have been visionary in this area. I would also like to thank Madeline Doyle and Martina Rudden from Goldshield for their commitment to the project and for their insight into using digital media to educate doctors.”

Contact: Peter Mas-Mollinedo on 00 353 872464977 or email peter@medicalimi.com

Peter Mas-Mollinedo, Managing Director IMI and Martina Rudden from Goldshield

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

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European Respiratory Society Reports from the ERS Annual Congress, Amsterdam by Bruce Sylvester

Environmental health risks of livestock farming More exacerbations in lung patients, Q fever risk increasing with number of livestock close by

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MISSIONS FROM livestock farms cause asthma and COPD patients living nearby to experience more exacerbations, according to research presented at the European Respiratory Society’s Annual Congress in Amsterdam.

Also, chances of contracting Q fever from nearby sheep and goat farms increased with the number of animals rather than with the number of farms, the research found, hinting at higher health risks from ‘mega farms’.

The researchers, from Utrecht University, measured increased levels of particulate matter containing microbes and microbial toxins near livestock farms. They studied health effects by screening medical records from 50 general practitioners servicing 200,000 patients in regions with high and low densities of livestock farms.

In regions with many livestock farms, doctors reported less asthma, COPD, upper respiratory tract infections and hay fever, a

result that mimics some earlier studies that saw less allergies in children who grown up on farms. In this study, the medical records did not specify whether symptoms were allergyrelated, so the researchers do not know whether the effect is indeed limited to allergies.

The research however also showed that in areas with many livestock farms, people who suffer from asthma or COPD developed twice as much pneumonia and upper respiratory tract infections than people in regions with little livestock activity. The overall prevalence of pneumonia was also higher in high-density areas.

The study period included an unusually severe outbreak of Q fever, an infectious disease of cattle, sheep or goats, which can cause flu-like symptoms and pneumonia in humans. Between 2007 and 2010, close to 4,000 people in the Netherlands became ill; at least ten of them died.

The researchers found that the risk of

contracting Q fever increased with the proximity of sheep farms or goat farms. An even stronger correlation was found between Q fever risk and the number of animals kept in the area, suggesting that mega farms could bring more environmental health risks than smaller farms.

The study contributes to on-going debates about intensive animal farming in densely populated regions in countries such as Germany and the Netherlands.

Lead researcher Dr. Lidwien Smit said: “Our study is one of the first to show that living close to farms leads to exacerbation of symptoms for people with lung conditions and that during a Q fever outbreak, the risk of contracting Q fever increased with the number of livestock animals kept close by.”

Source: Abstract: 3438 - Do emissions from animal farms affect the airways of neighbouring residents?

Session: Oral Presentation : Outdoor air pollution studies.

Alcohol can reduce asthma risk Drinking alcohol in moderate quantities can reduce the risk of asthma, according to Danish researchers

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HE STUDY, presented at the European Respiratory Society’s Annual Congress in Amsterdam, found that drinking one to six units of alcohol a week could reduce the risk of developing the condition.

The research examined 19,349 twins between the ages of 12 and 41 years of age. All participants completed a questionnaire at the start and end of the study to compare alcohol intake with the risk of developing asthma over eight years.

The results showed that the lowest risk of asthma was seen in the group which had a moderate intake of alcohol, as less than 4% of those who drank one - six units per week developed asthma.

The highest risk of asthma was observed in

24

people who drunk rarely or never, as they were 1.4 times more likely to develop the condition.

Heavy drinkers also had an increased risk of asthma development and were 1.2 times more likely to develop asthma.

The results also suggested that a preference for beer drinking was associated with an increased risk of asthma when compared with no preference.

Previous studies have found a link between excessive intake of alcohol and asthma attacks; however, this is the first study of its kind to show a link between alcohol intake and the onset of asthma for adults over a long period of time.

Sofie Lieberoth, from the Bispebjerg Hospital in Denmark, said: “Whilst excessive alcohol intake can cause health problems, the findings

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

of our study suggest that a moderate intake of one to six units can reduce the risk of developing asthma. By examining all the factors linked with the development of asthma, we can understand more about what causes the condition and how to prevent it.”

Source: Abstract: 319- Intake of alcohol and risk of adult-onset asthma. Session: Poster Discussion : Genetical and environmental risk factors for respiratory diseases.

New data show good efficacy and safety for combination in asthma patients

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HREE PHASE III studies demonstrate fluticasone/ formoterol combination (“flutiform®”) improves lung function and is effective at controlling asthma symptoms across different asthma severities in adolescents and adults aged 12 and above.

New data presented at the ERS congress show that flutiform®, a combination of fluticasone propionate (fluticasone), an inhaled corticosteroid (ICS), and formoterol fumarate (formoterol), a long-acting β2-agonist (LABA) therapy within a single aerosol inhaler: • had comparable efficacy in improving the lung function and a similar safety profile to budesonide/formoterol, a licensed combination asthma therapy.1 • was as effective in treating asthma as fluticasone and formoterol administered concurrently via separate inhalers. 2 • was more effective than each of the compounds administered alone on measures of lung function.3 Three Phase III studies for the fluticasone/formoterol combination were presented at ERS. The first study, a doubleblind, parallel group trial, compared the efficacy and safety of flutiform® with the budesonide/formoterol combination in 261 adolescents and adults with moderate-tosevere, persistent reversible asthma. This trial showed that the fluticasone/formoterol combination resulted in comparable improvement in change in morning pre-dose FEV1 (forced expiratory volume in 1 second), a common measurement of the lung function, from baseline to Week 12 to the budesonide/formoterol combination. The fluticasone/formoterol combination and the budesonide/formoterol combination were also shown to have similar safety profiles. 1 The second trial was an open-label, parallel group, European multicentre study, in adolescent and adult patients with mild to moderate-severe persistent, reversible asthma.

The study demonstrated non-inferiority of

the fluticasone/formoterol combination compared with the individual compounds administered concurrently based on postdose FEV1 on Day 84.2 Analysis of other efficacy endpoints, including, pulmonary function tests, patient reported outcomes, rescue medication use, asthma exacerbations and quality of life questionnaires, were also similar between study arms which involved 210 people with asthma.2 The third study measured the change in FEV1 from morning pre-dose at baseline to pre-dose at Week 12 seen with low-dose of the fluticasone/formoterol combination (100/10 µg b.i.d.) compared with formoterol (100 µg b.i.d.), and the change in FEV1 from morning pre-dose at baseline to two hours post-dose at Week 12 compared with fluticasone (100 µg b.i.d.), in 357 adult and adolescent patients with mild to moderate asthma. This doubleblind, parallel group, multicentre study, conducted in patients aged 12 and above, demonstrated superior efficacy of the fluticasone/formoterol combination compared to its individual compounds administered alone on these endpoints.3 “The benefits of ICS/LABA combination therapies are well established, with international clinical guidelines recognising their efficacy and role in improving patient adherence with ICS and asthma outcomes,” said Professor David Price, Centre of Academic Primary Care, University of Aberdeen, United Kingdom. “The data presented at ERS show the good efficacy and safety profile of the fluticasone/formoterol combination, which for the first time brings together these two molecules in a widelyused device, demonstrating its potential to become a valuable new treatment option for asthma patients.”

The new data presented at the ERS 2011 congress support previous studies which have demonstrated the efficacy and safety of the fluticasone/formoterol combination in adults and adolescents (aged 12 years and above).

The Marketing Authorisation Application

(MAA) for flutiform® has been submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) for approval and a decision is expected later this year.

Asthma, one of the most common chronic diseases in Europe, is associated with many deaths that could potentially be prevented with improvements in long-term asthma care.4,5,6 Despite a number of asthma treatments currently available many people with this condition are not optimally managed and are therefore at risk of exacerbations, considerably reduced quality of life and asthma-related mortality, all of which contribute to increased healthcare costs. 7 References: 1. Bodzenta-Lukaszyk A, et al. Fluticasone/formoterol combined in a single aerosol inhaler vs budesonide/formoterol for the treatment of asthma: a non-inferiority trial. Abstract presented at ERS, 2428.09 2011 in Amsterdam, Netherlands 2. Bodzenta-Lukaszyk A, et al. Fluticasone propionate/ formoterol fumarate combination therapy has comparable efficacy to its individual components administered concurrently. Abstract presented at ERS, 24-28.09 2011 in Amsterdam, Netherlands 3. Pearlman DS, et al. Fluticasone propionate/ formoterol fumarate combination therapy has superior efficacy to both fluticasone and formoterol alone. Abstract presented at ERS, 24-28.09 2011 in Amsterdam, Netherlands .

4. Global Initiative for Asthma (GINA). Global burden of asthma report. 2004. Available at: http://www.ginasthma.com/ReportItem.asp?l1=2&l 2=2&intId=94. Accessed on 22 August 2011 5. Masoli M, et al. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004 May;59(5):469-78 6. Braman SS. The global burden of asthma. Chest 2006;130(1 Suppl):4S-12S 7. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2010.

Available at: http://www.ginasthma.org/guidelinesgina-report-global-strategy-for-asthma.html.

Accessed on 22 August 2011 8. Bodzenta-Lukaszyk A, et al. Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler: Respiratory Medicine. 2011; 105:5, 674-682 9. Bodzenta-Lukaszyk A, et al. Fluticasone propionate/formoterol fumarate combination therapy is as effective as fluticasone propionate/salmeterol xinafoate, but has a more rapid onset of action in the treatment of asthma.

BMC Pulm Med. 2011. doi:1471-2466/11/28

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European Respiratory Society Reports from the ERS Annual Congress, Amsterdam by Bruce Sylvester

HRT appears to increase risk of hospitalisation from severe asthma attacks Women taking postmenopausal hormone replacement therapy (HRT) may have an increased risk of severe asthma attacks requiring hospitalisation, scientists warn

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NEW STUDY, presented at the European Respiratory Society’s Annual Congress in Amsterdam, adds to the debate over the health effects of the drug which helps women through the menopause.

Previous studies have found a link between asthma and HRT, but this is the first to suggest that the drug can lead to severe exacerbations of asthma, which could lead to hospitalisation.

Researchers Klaus Bønnelykke from COPSAC (the COpenhagen Prospective Studies on Asthma in Childhood) at the Danish Pediatric Asthma Centre and Zorana Jovanovic Andersen from the Danish Cancer Society recorded the intake of HRT in 23,138 women from the Danish Diet, Cancer and Health Cohort. They also denoted incidence of asthma hospitalisations and obtained information on participants’ smoking status, occupational exposure, body mass index and whether or not they had undergone a hysterectomy to account for other factors relating to asthma incidence.

The results showed that using HRT was positively associated with asthma hospitalisations, as women were 1.3-times more likely to be

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 Academy of Allergology & Clinical Immunology and European Respiratory 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

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EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

admitted to hospital for an exacerbation if they were taking the drug. The risk increased the longer HRT was used and women taking the drug for longer than ten years were 1.5 times more likely to require hospital treatment for asthma.

The results showed that using HRT was positively associated with asthma hospitalisations, as women were 1.3 times more likely to be admitted to hospital for an exacerbation if they were taking the drug.

These results were also found when taking into account other conflicting factors which could lead to a severe asthma exacerbation.

Dr. Klaus Bønnelykke, from COPSAC, said: “Previous research has suggested a link between asthma and female sex hormones, especially HRT. Our findings not only confirm this link, but also extend this to severe asthma exacerbations. We still need the final proof from randomised trials, but we believe that the suspicion is now so strong that it should be brought to the attention of clinicians. If a patient develops asthma or has a severe worsening of symptoms after taking HRT, they may need to stop hormone therapy altogether.”

Source: Abstract: 4111 - Late-breaking abstract: Postmenopausal hormone replacement therapy is associated with increased risk of asthma hospitalisation.

Session: Thematic Poster Session : Respiratory epidemiology: quality of life, therapy and socioeconomics

European Medicines Agency

highlights

by Gary Finnegan

European Parliament U-turn on EMA budget

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HE EUROPEAN Parliament has reversed its decision not to sign off on the European Medicines Agency’s budget.

MEPs sparked controversy earlier this year when they refused to endorse the Agency’s accounts, citing a lack of transparency in how the medicines regulator recruits staff and criticising the way it manages public procurement contracts.

The Parliament, which sits in Brussels and Strasbourg, had earlier accused the EMA of having “no proper guarantee of the independence of experts hired to carry out scientific evaluations of human medicines.”

MEPs are required to rubber-stamp the audited accounts of EU agencies and use their power of veto only on rare occasions. This year they singled out the EMA and the European Police College in Bramshill, UK, for their opaque approach to bookkeeping.

The Parliament also locked horns with the London-based EMA this summer after MEPs criticised one of its staff for a report written in the 1990s on the safety of an appetite suppressant which has since been removed from the market.

A number of French MEPs have publicly criticised the Agency’s experts, prompting the EMA’s Acting Executive Director Andreas Pott to publish lengthy defences of his staff.

The decision to approve the EMA’s accounts came after the Agency strengthened its rules on handling potential conflicts of interests of its staff and external experts. The agreement came on condition that the medicines regulator agrees to assess the impartiality of staff members appointed to evaluate medicines.

The issue is a complex one. The EMA has to use technical experts specialising in highly specific medical and scientific sub-disciplines with the knowledge to understand potential new medicines submitted to its committees for approval.

However, finding doctors and researchers –

with the competence to analyse complex clinical trial data – but who have never had contact with the medicines industry, is often a difficult task.

The sector is a major sponsor of clinical studies, research grants and conferences meaning many investigators have engaged with industry on some level, while some of those who have had no such contact have too little relevant experience.

MEPs on the Budget Control Committee also insisted on being kept informed on improvements in the areas of procurement procedures.

Less red tape for small businesses Small and medium-sized enterprises (SMEs) will face fewer administrative hurdles when registering with the European Medicines Agency.

The European Medicines Agency has been working over the past five years to make it easier and cheaper for smaller firms to bring their innovations to market.

This followed criticism from business groups and politicians that red tape was giving larger corporations an advantage as they were the only companies with the resources to deal with the administrative burden.

A new electronic-only submission process has now been introduced and SMEs will have to file fewer documents when submitting a medicine for review.

More than 600 companies are currently registered for special treatment with the Agency through its dedicated SME office.

New medicines approved The EMA’s key drug-approval body – the Committee for Medicinal Products for Human Use (CHMP) – has given the green light to a number of new products.

The Committee gave its approval to Ameluz (78mg/g gel) intended for the treatment of actinic keratosis.

Ameluz, marketed by Biofrontera Bioscience GmbH, is 5-aminolevulinic acid hydrochloride, a

sensitizer used in photodynamic/radiation therapy (L01XD04) that causes damage of cellular components and eventually destroys the target cells.

The benefits with Ameluz are its ability to improve the complete response rate of actinic keratosis lesions, according to the CHMP. The most common side effects are irritation, erythema, pain, pruritus, oedema, exfoliation, scab and induration at application site.

The Committee also approved Bronchitol (40mg inhalation powder, hard capsules) intended for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.

Bronchitol, produced by Pharmaxis Pharmaceuticals Ltd., was designated as an orphan medicinal product on 7 November 2005. The active substance of Bronchitol is mannitol, an hyperosmolar agent (R05CB16) which is understood to change the viscoelastic properties of mucus, increase the hydration of the periciliary fluid layer and contribute to increased mucociliary clearance of the retained secretions.

The benefits with Bronchitol are its ability to improve lung function, according to the CHMP. “Although the size of the effect is small with around 2-3% absolute change in FEV1 predicted and the clinical benefit is difficult to ascertain, it is acknowledged that even a small effect can be of relevance given the deterioration of FEV1 inherent to the disease progression,” the EMA said in a statement.

The marketing authorisation for Cervarix, a cervical cancer vaccine produced by GSK Biologicals, has been updated to allow it to be administered to children from nine years of age.

The vaccine is proven to help prevent premalignant cervical lesions and cervical cancer causally related to certain oncogenic Human Papillomavirus (HPV) types.

All recommendations of the EMA’s CHMP will have to be formally endorsed by the European Commission in Brussels.

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Journal reviews

by Bruce Sylvester

Reporting from some of the latest articles in

www.nejm.org

Medical management could be best for stroke prevention: SAMMPRIS study

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ATIENTS WITH narrowed brain arteries receiving intensive medical treatment had fewer strokes and deaths than patients receiving a brain stent in addition to medical treatment, researchers reported on Sept. 7 in the Online First edition of the NEJM. The results come from the (US) National Institutes of Health (NIH) study called Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS).

"Stenting was associated with a higher stroke and death rate at 30 days versus aggressive medical management alone," said Shyam Prabhakaran, MD, neurologist and investigator at Rush University Medical Center in Chicago.

"At this time, stenting cannot be supported in routine practice; however, whether subgroups may benefit from this or other interventions in the future needs further study."

The study design for medical management of all subjects included a daily dosage of 325mg of aspirin, and 75mg a day of clopidogrel for 90 days after enrollment. Also, patients received aggressive management of key stroke risk factors including high blood pressure and high levels of low density lipoprotein (LDL). All patients participated in a lifestyle modification programme focused on

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smoking, exercise, and controlling diabetes and cholesterol.

Half of the subjects received a self-expanding stent that widens the major artery in the brain and helps blood flow. The device used in the study, called the Gateway-Wingspan intracranial angioplasty and stenting system, is the only system currently FDA approved for certain high-risk stroke patients.

SAMMPRIS investigators enrolled 451 patients at 50 hospital sites in the U.S. The endpoint of the study was second stroke or death within 30 days of enrollment, or a stroke in the same area of the brain from 30 days after enrollment to the end of follow-up.

Subjects were in the highest stroke risk category, with blockage or narrowing of the arteries from 70-99%.

Subjects were between 30 and 80 years of age and had experienced a recent transient ischaemic attack that resolved within 24 hours, or another type of non-disabling stroke, caused by stenosis in the cerebral artery.

"At this time, stenting cannot be supported in routine practice; however, whether subgroups may benefit from this or other interventions in the future needs further study."

The investigators hypothesised that addition of intracranial stenting to intensive medical therapy would decrease the risk of stroke of death by 35% over two years.

Instead, they found that 14.7% of patients in the stenting group experienced a stroke or died, compared to the 5.8% of patients treated only with drug therapy.

New enrollment in the study was halted in April since early findings suggested that strokes and deaths occurred more significantly among the stented patients. All patients who participated in the trial will continue to be followed for two years to determine longerterm effects of both interventions.

"The SAMMPRIS study is a call to arms to all physicians caring for patients with this high risk condition. It provides evidence that highly effective medications when used in combination

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and when strict targets for risk factor modification are met can have substantial stroke prevention benefits," said Dr. Prabhakaran.

www.jama.ama-assn.org

Annual screening with chest x-ray fails to lower rate of lung cancer deaths

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NNUAL CHEST radiographic screening for up to 4 years did not significantly lower the rate of death from lung cancer among screened subjects when compared to participants who were not screened, according to a large study published in the November 2 issue of JAMA. The study was also featured at the annual meeting of the American College of Chest Physicians (CHEST 2011).

"Lung cancer is the leading cause of cancer death in the United States and worldwide.

Screening for lung cancer has long been studied as an approach to reducing the burden of lung cancer," the authors noted in background to their report. "The effect on mortality of screening for lung cancer with modern chest radiographs is unknown," they added.

In the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Martin M. Oken, M.D., of the University of Minnesota, and colleagues studied effects on mortality in lung cancer by screening with radiographs. The randomised controlled trial enrolled 154,901 subjects, ages 55 through 74 years, of whom 77,445 were assigned to annual screenings and 77,456 to usual care at centres across the United States, between November 1993 and July 2001.

About half of the subjects were female (50.5%); about 45% were never smokers, 42% former smokers, and 10% current smokers.

Subjects randomised to x-rays were offered an annual chest x-ray for four years. Follow-up treatment after of positive screenings was determined by each subject and their health care provider.

Usual care subjects were offered no chest x-ray screening and received their usual medical care.

All diagnosed cancers, deaths, and causes of death were determined through the earlier of 13 years of follow-up or until December 31, 2009.

There was an adherence-to-screening rate of 86.6% at the beginning of the trial, decreasing to 79% by year three. The overall adherence rate was 83.5%.

During the 13 year study period, the investigators found 1,696 lung cancers in the radiograph group and 1,620 lung cancers in the usual care group. Stage and histology was similar by group, with about 41% being adenocarcinoma, 20% squamous cell carcinoma, 14% small cell carcinoma, 5% large cell carcinoma, and 20% other non-small cell lung cancer.

The researchers reported that annual chest radiographic screening for up to four years did not significantly decrease lung cancer mortality compared with usual care. During the 13-year follow-up period there were 1,213 lung cancer deaths in the radiographic screening group vs.

1,230 in the usual care group.

"Therefore, these findings provide good evidence that there is not a substantial lung cancer mortality benefit from lung cancer screening with annual chest radiographs," the authors concluded.

BMJ www.bmj.org

Some contraceptive pills appear to raise blood clot risk

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RETROSPECTIVE STUDY published online on Oct. 25 in the BMJ confirms that some oral contraceptive pills increase the risk of serious blood clots (venous thromboembolism/VTE).

The investigators, led by Dr. Øjvind Lidegaard from the University of Copenhagen, concluded that pills containing newer types of progestogen hormone (drospirenone, desogestrel or gestodene) double the risk of VTE compared with pills containing an older progestogen (levonorgestrel).

Dr. Lidegaard and his team reviewed data of the hormonal contraception patterns and first time VTE episodes for all Danish non-pregnant women between the ages of 15 and 49 from January 2001 until December 2009. Subjects had no record of either blood clots or cancer prior to the evaluation period.

The researchers analysed over eight million women-years of observation, finding 4,246 first episodes of VTE. When compared with non-users of hormonal contraception, pills with levonorgestrel increased the risk of VTE threefold, and pills with drospirenone, desogestrel or gestodene increased the risk six-fold.

Notably, in absolute terms, the risk of VTE

among current users of newer pills was about 10 per 10,000 women years. This means that about 2,000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of VTE in one year.

The increased risk remained evident even after the investigators factored in other possible causes of VTE.

When compared with non-users of hormonal contraception, pills with levonorgestrel increased the risk of VTE three-fold...

In an accompanying editorial, Philip Hannaford, MD, from the University of Aberdeen said, "it is difficult not to conclude that combined oral contraceptives with desogestrel, gestodene or drospirenone confer a higher risk of venous thromboembolism than those with levonorgestrel" and that "many clinicians will choose to minimize the risk by prescribing a combined oral contraceptive with levonorgestrel whenever possible."

But Dr. Hannaford noted that it is crucial, "not to exaggerate the risk - oral contraceptives are remarkably safe and may confer important long-term benefits in relations to cancer and mortality."

www.thelancet.com

Aspirin halves hereditary cancer risk

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ESEARCHERS REPORTED in The Lancet on Oct. 28 that regular aspirin use halves the risk of developing hereditary cancers, those cancers which develop as a result of a gene fault inherited from a parent. Bowel and womb cancers are the most common forms of hereditary cancers.

The investigators tracked nearly 1,000 patients, in some cases for over ten years. The study took place at 43 centres in 16 countries; it was funded by Cancer Research UK.

The research focused on people with Lynch syndrome, an inherited genetic disorder causing cancer by affecting genes responsible for detecting and repairing damage in the DNA. About 50% of those with Lynch syndrome develop cancer, mainly in the bowel and womb.

The investigators analysed data for all cancers related to the syndrome, and they found that almost 30% of subjects not taking aspirin had developed a cancer compared to around 15% of those taking aspirin.

The aspirin users developed the same number of polyps, thought to be precursors of cancer, as those who did not take aspirin, but they did not go on to develop cancer. This suggests that that aspirin might be causing these cells to destruct before they turn cancerous.

Patrick Morrison, MD, of Queen's University in Belfast, who led the Northern Ireland part of the study said, "The results of this study, which has been ongoing for over a decade, proves that the regular intake of aspirin over a prolonged period halves the risk of developing hereditary cancers. The effects of aspirin in the first five years of the study were not clear but in those who took aspirin for between five and ten years the results were very clear."

Dr. Morrison continued, "This is a huge breakthrough in terms of cancer prevention.

For those who have a history of hereditary

This suggests that that aspirin might be causing these cells to destruct before they turn cancerous.

cancers in their family, like bowel and womb cancers, this will be welcome news. Not only does it show we can reduce cancer rates and ultimately deaths, it opens up other avenues for further cancer prevention research. We aim now to go forward with another trial to assess the most effective dosage of aspirin for hereditary cancer prevention and to look at the use of aspirin in the general population as a way of reducing the risk of bowel cancer. For anyone considering taking aspirin I would recommend discussing this with your GP first as aspirin is known to bring with it a risk of stomach complaints, including ulcers.”

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

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Medical news from around the world

by Gary Finnegan

World Health Matters CANADA Hospital smoking bans called into question THE BENEFIT OF BANNING smoking in hospitals may be outweighed by a series of unforeseen consequences, according to Canadian researchers.

Researchers say more should be done to support patients facing nicotine withdrawal and to guard against practical problems thrown up by making hospitals smoke-free zones.

Smoking bans have been introduced across much of Europe and North America, often led by vocal medical campaigners who have highlighted the health risks of tobacco use.

Smoking bans have been introduced across much of Europe and North America, often led by vocal medical campaigners who have highlighted the health risks of tobacco use.

Workplace smoking bans extend to hospitals in most countries and health authorities have typically viewed it as counterproductive to entertain the idea of making hospitals exempt from a ban on a known carcinogen.

However, new research in Canada has revealed several cases where intravenous lines and electronic equipment have frozen when patients have gone outdoors for a cigarette, as well as instances where patients were locked out overnight in the cold Canadian winter.

The study by the University of Alberta Hospital in Edmonton and Winnipeg’s Health Sciences Centre said the ban is routinely ignored by patients and staff in some hospitals due to the impact of withdrawal symptoms.

People who are hospitalised are often plunged into sudden nicotine withdrawal which

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can affect their state of mind at a time when they are dealing with other illnesses.

Nicotine use, say the authors, should be treated like an addiction rather than a bad habit.

The research is based on interviews with 186 patients, staff and hospital staff – including housekeepers, security guards and groundskeepers, described in the paper as “key informants” due to the wealth of information they have on how patients have flouted the smoking ban by sneaking cigarettes into their rooms and in “smoke free” areas on hospital grounds.

Patients are not the only ones to defy the rules. “Staff who had reportedly been seen smoking on hospital property included security guards, ambulance drivers, nurses and doctors,” the authors write in the Canadian Medical Association Journal.

Hospital cleaning staff said they routinely collect large quantities of discarded cigarette butts in smoke-free hospitals while nurses and hospital porters complain that too much time is consumed by patients asking to be brought outside for a cigarette.

There are also wider public health risks associated with patients smoking outside, according to the paper, including the dangers posed by tuberculosis patients – who are supposed to be kept in isolation – discarding cigarette butts in hospital car parks.

The authors call for the problem to be viewed in the round in light of the unintended negative consequences that have arisen from the hospital smoking ban, and also call for greater support for public anti-smoking campaigns.

CHINA Newborn death rate halved thanks to hospital births A NEW SAFE MOTHERHOOD policy in China to promote hospital births has slashed the neonatal death rate.

Chinese authorities began the programme ten years ago amid concerns that mothers, particularly in poorer areas of China where

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

basic sanitation standards are low, were facing higher risks of infection.

Most babies are now born in hospitals, with the exception of the very poorest socioeconomic groups, some of whom are based in remote rural areas.

Comparing figures from 1996 and 2008, the mortality rate in neonates fell by 62% while hospital delivery soared.

While the number of deaths in children under five has declined globally over the past decade, neonatal deaths – which occur mostly in low-income and middle-income countries – have increased and account for 41% of all deaths in this age group.

Strategies to improve newborn survival in low-income countries have mainly focused on community and outreach interventions, and little is known about the potential effect of large-scale hospital-based strategies on newborn deaths, according to the authors.

Over the past 15 years, China's success in improving the quality and access to obstetric care in hospitals has greatly reduced maternal deaths, but until now its effect on neonatal mortality was not known.

Xing Lin Feng and Yan Guo from Peking University, Beijing, China, and Carine Ronsmans from the London School of Hygiene and Tropical Medicine, London, UK, led a team to try and establish the impact of China's hospitalbased birth strategy on newborn survival.

Between 1996 and 2008, they examined trends in neonatal mortality by cause and socioeconomic region, using data from China's Maternal and Child Mortality Surveillance System (MCMS).

In all regions, hospital births were much safer than home births, with babies born in hospital two to three times less likely to die than babies born at home, irrespective of the socioeconomic region or cause of death (except congenital abnormalities).

However, findings also showed that babies born in hospitals in the poorer rural areas remained almost four times more likely to die

than babies born in urban hospitals, where rates of neonatal mortality were low (5.7 per 1000 live births).

The authors suggest that this could be the result of lower quality hospital care, lack of resources and the dearth of skilled personnel in rural areas or that facility-based care was sought too late in the poorest areas.

“Other countries can learn from China's substantial progress in reducing neonatal mortality. The major effect of China's facilitybased strategy on neonatal mortality is much greater than that reported for communitybased interventions,” the researchers say.

However, they note that further improvements are still needed particularly in rural areas where access to hospitals remains patchy.

FINLAND New thinking on early diabetes detection A STUDY BY FINNISH researchers has opened a new potential avenue which could ultimately lead to earlier detection and prevention of autoimmune diabetes.

The research, led by Matej Orešicˇ from the VTT Technical Research Centre of Finland suggests that autoimmune diabetes is

Translation: doctors could potentially use changes in bacteria levels in the gut as an early warning system for diabetes.

preceded by a reduction in gut microbial diversity of the Clostridium leptum subgroup, elevated plasma leptin and enhanced glucosestimulated insulin secretion.

Translation: doctors could potentially use changes in bacteria levels in the gut as an early warning system for diabetes.

As part of the Finnish Type 1 Diabetes and Prediction study, the research team has previously found that specific metabolic disturbances precede early β-cell autoimmunity markers in children who subsequently progress to Type 1 diabetes.

However, until now it was not clear what environmental factors and tissue-specific mechanisms lead to these disturbances.

In a paper published in the PLoS Computational Biology journal, scientists found that young female non-obese diabetic (NOD) mice which later progress to autoimmune diabetes exhibit the same metabolic pattern as prediabetic children.

These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and changes in levels of the Clostridium leptum subgroup of bacteria in the gut.

This new information on the early metabolic pathways associated with progression to Type 1 diabetes points to novel avenues for early disease prevention, according to the authors of the study.

The incidence of inflammatory and autoimmune diseases is rising faster than for any other major disease, and these diseases are affecting a wide spectrum of the population.

The number of new cases of Type 1 diabetes in European children less than five years of age is expected to double between 2005 and 2020, according to the authors.

The research team behind the study are now looking at the potential of specific bacteria from the C. leptum subgroup to help prevent Type 1 diabetes.

FRANCE Boost for remote follow-up of ICD patients A NEW FRENCH STUDY has shown significant benefits of remote follow-up of patients with implantable cardioverter-defibrillators (ICD).

Results from the EVATEL (EVAluation of TELe follow-up) trial are the first in Europe to demonstrate potential safety and efficacy benefits from the remote follow-up of ICD patients.

ICDs are devices routinely implanted in patients at risk of sudden cardiac death as a result of rhythm disturbances. The expanding indications for ICDs are expected to have an impact on follow-up strategy, as the number of patients with ICDs is increasing rapidly.

“Currently, regular in-clinic follow-up must be performed every three months, according to manufacturer guidelines,” explained Dr. Philippe Mabo from the University Hospital of Rennes,

France, “but there are two drawbacks to the inclinic follow-up: it’s time-consuming for both the patient and the clinic, and there’s no link between the time of the appointment and the clinical event or device malfunction. So there's a clinical need to consider new follow-up strategy.”

In response, several manufacturers have developed new technologies which allow the remote transmission of information from the device and on its therapeutic effect.

Critical data can be transmitted at any time on system integrity or unexpected events - for example, lead integrity, battery status or ineffectively delivered therapy. Data stored in the device are transmitted by phone from the patient's home to the implant centre, with website access to the data.

“Currently, regular in-clinic follow-up must be performed every three months, according to manufacturer guidelines.”

“In this context,” said Dr. Mabo, “remote device follow-up seems to be a promising technique for device follow-up. But the technology needed clinical validation in terms of safety, efficacy and cost-efficiency, which were the objectives of the EVATEL trial.”

The study, which was funded by the French government, included 1,501 patients from 30 French centres enrolled between January 2008 and January 2010. They were each followed-up every three months for an overall period of one year. The last follow-up was performed in January 2011.

Half the patients received conventional follow-up at the implant centre, the other half were followed remotely.

No significant difference in death rates was seen between the group and the one-year survival rates were also similar.

Commenting on the results, Dr. Mabo said: “The remote follow-up of patients implanted with an ICD seems to be a safe alternative to conventional in-office follow-up. However, for the widespread uptake of this new strategy - at least in France - reimbursement from the healthcare system will be needed. We hope that it will be available soon in France.”

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

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FDA highlights

by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs Atypical antipsychotics effective for only a few off-label uses

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N A REVIEW of previous studies, researchers conclude that atypical antipsychotic medications are effective in a few off-label uses. The findings were published in the September 28 issue of JAMA.

"Atypical antipsychotic medications are approved for marketing and labeling by the U.S. Food and Drug Administration (FDA) for treating schizophrenia, bipolar disorder, and depression under drug-specific circumstances. “

As background, the authors noted, "Atypical antipsychotic medications are approved for marketing and labeling by the U.S. Food and Drug Administration (FDA) for treating schizophrenia, bipolar disorder, and depression under drug-specific circumstances. The use of atypical antipsychotic medications is rapidly increasing in the United States, with one study estimating an increase from 6.2 million to 14.3 million treatment visits between 1995 and 2008. The estimated use of these drugs for offlabel indications, meaning those without FDA approval for these indications, doubled during this period."

Alicia Ruelaz Maher, M.D., of RAND Health, Santa Monica, California, and colleagues conducted the meta-analysis. They analysed the data to determine efficacy and adverse events associated with off-label use of atypical antipsychotic medications for behavioural symptoms in dementia, anxiety, obsessive-

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compulsive disorder (OCD), eating disorders, post-traumatic stress disorder (PTSD), insomnia, personality disorders, depression, and substance abuse.

The investigators scanned the medical literature for controlled trials comparing an atypical antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions.

To assess adverse events, they included observational studies with populations over 1,000 subjects.

They included 162 trials with efficacy outcomes, and they included 231 trials or large observational studies with adverse events.

They reported that aripiprazole, olanzapine, and risperidone were associated with small but statistically significant benefits for the treatment in elderly patients of behavioural symptoms of dementia, such as psychosis, mood alterations, and aggression. For generalised anxiety disorder, pooled data from three trials showed that quetiapine was associated with a 26% increase in favourable response at 8 weeks compared with placebo. For obsessive-compulsive disorder, three pooled studies of risperidone resulted in about a four-fold increase in response compared with placebo. There was no clear evidence to support the use of atypical antipsychotics for substance abuse or eating disorders.

"In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH] = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms [movement disorders; NNH = 10 for olanzapine; NNH = 20 for risperidone], and urinary tract symptoms (NNH range-16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia [inability to remain motionless] (for aripiprazole), and extrapyramidal symptoms," the authors noted.

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"The benefits and harms vary among atypical antipsychotic medications for off-label use," they concluded. "This evidence should prove useful for clinicians considering off-label prescribing of atypical antipsychotic medications, and should contribute to optimal treatment decision making for individual patients with specific clinical symptoms and unique risk profiles."

Acne drug reduces catheter infections among dialysis patients

R

ESEARCHERS REPORT that an antibiotic routinely used to treat acne could safely prevent bacterial infections in dialysis patients.

The results of the study by Rodrigo Peixoto Campos, MD, of the Pontifícia Universidade Católica do Paraná, Curitiba, Brazil, and colleagues appears in the November 2011 issue of the Journal of the American Society Nephrology (JASN).

“When a dialysis clinic cannot achieve lower rates of catheterrelated bacterial infections with routine catheter care protocols, the use of a catheter lock solution of minocycline-EDTA may be the next step to reduce this major complication...”

As background, the authors noted that, after dialysis, a catheter is “locked” to prevent blood clots from forming within the device. A lock is usually made by injecting heparin into the catheter.

In this randomised, controlled study of over 200 patients, the investigators compared heparin with a solution made up of the antibiotic minocycline and the chemical EDTA.

Half of subjects had catheter locks containing the novel combination and the other half had catheter locks containing only heparin.

Minocycline is routinely used to treat acne, and EDTA improves the action of antibiotics, fights fungal infections and prevents blood clots.

Half of subjects had catheter locks containing the novel combination and the other half had catheter locks containing only heparin.

The investigators reported during the 90-day study period, that bacterial infections developed in the catheters of 19 patients in the heparin group compared with only five patients in the minocycline-EDTA group. Also, the catheters functioned similarly in both group.

“When a dialysis clinic cannot achieve lower rates of catheter-related bacterial infections with routine catheter care protocols, the use of a catheter lock solution of minocycline-EDTA may be the next step to reduce this major complication, without the apprehension of developing bacterial resistance to systemic antibiotics,” said Dr. Campos.

Zoledronic acid stops bone loss in some breast cancer drug treatment

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OLEDRONIC ACID protects against the bone damaging side effects of certain breast cancer medications, researchers reported in a study published early online on Oct. 10, 2011 in Cancer.

Adam Brufsky, MD University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, and colleagues conducted the five-year study. They enrolled 602 postmenopausal women with early breast cancer who were receiving letrozole. They randomised the subjects to

receive either zoledronic acid simultaneously with letrozole or only when bone loss or fractures occurred.

The investigators reported significant and progressive increases in bone density throughout the five years among the women who initiated zoledronic acid at the beginning of the study. They found significant decreases in bone density among the other women.

Over time, though, bone density decline slowed in the delayed group. The investigators hypothosised that this might be due to the fact that more delayed patients received zoledronic acid by the end of the study.

The investigators concluded that bone density is maintained more effectively with upfront zoledronic acid, but initiating zoledronic acid, even after bone loss has developed, can be beneficial.

“This study shows that bone loss from aromatase inhibitors can be prevented long term with a safe and effective drug that prevents osteoporosis,” said Dr. Brufsky.

Drug combo prolongs life in chronic lymphocytic leukaemia

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OMPARED WITH fludarabine monotherapy, combination fludarabine and alemtuzumab significantly increases progression-free survival in chronic lymphocytic leukaemia (CLL) patients, and it and prolongs the lives of those who have relapsed.

“Unlike common regimens used to treat CLL, the new two-drug combination spares patients from the toxicities of additional alkylating drugs.”

The findings were published online first on Oct. 11 in The Lancet Oncology.

“Unlike common regimens used to treat CLL, the new two-drug combination spares patients from the toxicities of additional

alkylating drugs,” said lead author Thomas Elter, MD, University of Cologne, Cologne, Germany. “Moreover, the required dose of each drug is lower when used in combination than when the drugs are used alone, and the dosing schedule of three days a month is more convenient for patients than the standard regimen of three times a week for up to 12 weeks.”

As background, the authors noted that a great diversity exits among patients with CLL, in terms of disease burden, age, and co-occurring illnesses. So, there is no single standard treatment for all patients with CLL and additional treatment options are needed.

In this phase III trial, the investigators randomised subjects with CLL (from North America and Europe) to fludarabine plus alemtuzumab (n = 168) or fludarabine alone (n = 167), for a maximum of six 28-day cycles of treatment.

The researchers found that progressionfree survival (23.7months vs 16.5 months) and overall survival were significantly improved with the combination treatment than with fludarabine monotherapy.

Complete response rates were also much improved with the combination.

Notably, older patients and patients with advanced disease also benefited from the combination regimen.

The researchers reported similar frequency of grade three or four neutropaenia and thrombocytopaenia. But anaemia was lower in the combination group (9% vs 17%), and lymphopaenia (94% vs 33%) was more common.

The incidence of serious adverse events was higher in the combination group (33% vs 25%), but the number of subjects who discontinued treatment and died during treatment was similar in both groups.

“The combination of fludarabine and alemtuzumab is another treatment option for patients with previously treated CLL,” the authors concluded.

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

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View from the waiting room

by Steve Devrell

Dying to live for ever

A

S A CHILD, I remember watching the beautiful Ursula Andress age in seconds before my very eyes; she was 3000 years old! That film scene from Ryder Haggard’s SHE, fascinated me then and now, as I enter the final few laps of life expectancy, my interest in the concept of immortality has become, as one might expect, a little more pertinent.

Is immortality a work of fiction and religion, or is it an achievable goal? Well it depends very much on who you listen to.

Is immortality a work of fiction and religion, or is it an achievable goal? Well it depends very much on who you listen to. Some eminent academics believe it is still an amusing pipe dream while others like Dr. Ronald Klatz, MD who is the president of the American Academy of AntiAging Medicine believes human immortality is achievable by the year 2029. Perhaps the most prominent advocate of immortality is a Cambridge academic with the rather unwieldy name of Dr. Aubrey David Nicholas Jasper de Grey.

In every sense, de Grey can be described as an eccentric. In a recent Channel Four programme, the Rasputin-like figure is seen punting down the River Cam clutching a can of Old Speckled Hen. His mother, an equally eccentric looking artist from Chelsea, is interviewed about the brilliance of her son, whilst cuddling a large teddy bear. Unconventional maybe, but is he just another of the ground-breaking innovators and geniuses who have been mocked in their lifetime and hampered by the terminology of eccentricity?

De Grey sees immortality as just another step in the evolutionary process and space exploration a way of dealing with the over-population issue caused by immortality. He

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believes if funding is made available, there is someone alive today who will live for 1,000 years. Research has already altered the genes in dwarf mice so that they could live for 140 years and the jellyfish is able to enjoy a rebirth after reproduction that could lead to its immortality. One of de Grey’s more peculiar recommendations is that, in time, people may have to find someone else who is prepared to die before they can have a child. This ‘exchange’ would be a short-term measure to combat over-population until other habitable planets can be found.

De Grey highlights seven types of aging damage (The Seven Deadly Things) that would need to be addressed before immortality becomes a possibility: 1. Cancer causing nuclear mutations/epimutations – these are changes to the nuclear DNA, the molecule that contains our genetic information.

2. Mitochondrial mutations – indirectly, these mutations may accelerate many aspects of aging.

3. Intracellular aggregates – those molecules which can’t be digested simply accumulate as junk inside our cells and all kinds of neurodegenerative diseases (such as Alzheimer’s disease) are associated with this problem.

4. Extracellular aggregates – harmful junk products can also accumulate outside our cells.

5. Cell loss – some of the cells in our bodies cannot be replaced, or can only be replaced very slowly – more slowly than they die. This decrease in cell numbers causes the heart to become weaker with age.

6. Cell senescence – this is the phenomenon where the cells are no longer able to divide, but also do not die and let others divide.

7. Extracellular cross-links – cells are held together by special linking proteins. When too many cross-links form between cells in a tissue, the tissue can lose elasticity and cause problems.

But even if The Seven Deadly Things could be eradicated, would immortality be such a desirable objective? If you were to ask the majority of people if they would want to live forever they would probably answer ‘No’, but that is an easy thing to say when you know in all probability that you have a lot of life left. Older people and chronically ill people

may also answer negatively because they see their life as just an extension of their present condition. But if the technology was available to restore, replace and rejuvenate, would immortality be such a bad thing?

The absence of aging would provide humans with biological immortality, but not invulnerability to death by physical trauma. Under these circumstances, would people be less willing to explore and take physical risks?

There are however, many ethical and practical problems associated with immortality. As long as religion has an influence on the moral code of society, immortality could be viewed as undesirable, even unnecessary. In so many major religions like Judaism, Hinduism, Islam, Sikhism and Christianity, an afterlife or immortality is a fundamental tenet of their belief only God can grant immortality.

The problem of over-population is one that could not be conventionally solved in the foreseeable future. So would we have enough food, resources or even room to accommodate a rapidly increasing population? Also much of our social and technological development has resulted from the fact that people have wanted to leave an enduring legacy from their comparatively short time on earth. Would the ambition and drive necessary to leave this footprint disappear if life was extended indefinitely? Max Planck, the German physicist, recognised this point with the quote – ‘Science makes progress by funerals.’

The absence of aging would provide humans with biological immortality, but not invulnerability to death by physical trauma. Under these circumstances, would people be less willing to explore and take physical risks? Or perhaps there

might be a reluctance to perform the essential but potentially dangerous jobs that could result in permanent death? Would all our policemen, soldiers, airline pilots suddenly become librarians or Avon reps? Under these circumstances, our society could become stagnant and potentially lawless.

So, is immortality part of an evolutionary process, or part of a revolutionary process? I would wager that the concept will be achievable before it is acceptable. A much more likely scenario would be the extension of life with improvements to its quality.

Life extension science is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan. Many researchers in this area believe that future breakthroughs in tissue rejuvenation with stem cells, molecular repair and organ replacement (such as with artificial organs or xenotransplantation) will eventually enable humans to have indefinite life spans through complete rejuvenation, but this is not a short-term option. The maximum lifespan for humans is currently maximised at approximately 120 years. For this to be improved upon, the most challenging factor remains the telomere limitations for humans. In the meantime, it is the recommended life extenders and enhancers like improved medical care, a good diet, exercise and the avoidance of harmful substances like tobacco that are the major influences on prolonging life.

Incidentally a recently deceased 115 year old lady donated her body to science and it was found that through mapping her DNA, she had genes that may ensure a long life and protect her against dementia. Pretty good going really when one finds out that she was born prematurely and was not expected to survive. The relatively new development of DNA mapping, (the process is barely more than 10 years old), is another major advancement in the study and prevention of aging.

Whatever the future prospects might be for immortality, I’m personally not holding my breath, (a pretty foolish thing to do anyway if I was planning to extend my life)! But I am certain that such an option will one day be available, but unfortunately not in my life time. So as far as I’m concerned, it’s full steam ahead for the funeral arrangements.

I want no flowers or any of the currently popular songs chosen for funerals:My Way. Well maybe!

Unforgettable. I doubt it.

My Heart will go on. It won’t!

EVIDENTIA • VOLUME 5 • ISSUE 6 • NOVEMBER/DECEMBER 2011

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Tell me Nathan, how does FOSTAIR

Now licensed for use with AeroChamber Plus

feel?

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

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

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

effects of inhaled corticosteroids may occur, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhaled than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma. Titrate to the lowest dose at which effective control of asthma is maintained to minimise systemic effects. Special care is needed in transferring patients from oral steroids. Fostair contains a small amount of ethanol (approximately 7mg per actuation); at normal doses the amount of ethanol is negligible and does not pose a risk to patients. Patients should rinse mouth after inhalation to minimise risk of oropharyngeal candida infection. Drug interactions: Beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes without involvement of the cytochrome p450 system. Avoid beta-blockers (including eye drops). Caution is required when theophylline or other beta-adrenergic drugs are prescribed concomitantly with formoterol. Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, MAOIs and TCAs can prolong the QTc interval and increase the risk of ventricular arrhythmias.

In addition, L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance.

Concomitant administration with MAOIs, including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertension. Risk of arrhythmias in patients receiving anaesthesia with halogenated hydrocarbons. Theoretical potential for interaction in sensitive patients taking disulfiram or metronidazole. Pregnancy and Lactation: No experience. Balance risks with benefits. Side effects: Common: pharyngitis, headache, dysphonia. Uncommon: influenza, oral fungal infection, pharyngeal and oesophageal candidiasis, vaginal candidiasis, gastroenteritis, sinusitis, granulocytopenia, dermatitis allergic, hypokalaemia, hyperglycaemia, restlessness, tremor, dizziness, otosalpingitis, cardiac arrhythmias, hyperaemia, flushing, rhinitis, cough, productive cough, throat irritation, asthmatic crisis, pruritus, rash, hyperhidrosis, diarrhoea, dry mouth, dyspepsia, dysphagia, burning sensation of the lips, nausea, dysgeusia, muscle spasms, myalgia, C-reactive protein increased, platelet count increased, free fatty acids increased, blood insulin increased, blood ketone body increased. Rare: ventricular extrasystoles, angina pectoris, paradoxical bronchospasm, urticaria, angioneurotic oedema, nephritis, blood pressure increased, blood pressure decreased. Very rare: thrombocytopenia, hypersensitivity reactions, adrenal suppression, abnormal behaviour, sleep disorder, hallucination, glaucoma,

cataract, atrial fibrillation, dyspnoea, exacerbation of asthma, growth retardation in children and adolescents, peripheral oedema, bone density decreased. Legal Category: POM Packs and Prices: Fostair 100/6 (PL08829/0156) £29.32. Each inhaler contains 120 actuations. Full prescribing information is available from the Marketing Authorisation Holder: Chiesi Limited, Cheadle Royal Business Park, Highfield, Cheadle, SK8 3GY. Date of preparation: January 2011.

REFERENCES 1. De Backer W, Devolder A, Poli G et al. Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic and COPD patients. J Aerosol Med Pulm Drug Deliv 2010; 23(3): 137-148.

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

Clin Immunother 1996; 6: 273-299.

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

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

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

AeroChamber PlusTM is a licensed trademark of Trudell Medical International.

Date of preparation: JANUARY 2011 | Job code: CHFOS20110090

Adverse events should be reported.

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

Tel: 0161 488 5555.

TM