Volume 5 Issue 6 |

November/December 2011 |

ISSN 1753-464X

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

Emissions from livestockfarms cause greaterexacerbations in COPD and asthma patients

Aspirin halves hereditarycancer risk

Overweight children havethree times the risk of high blood pressure

Conference reports from: Amsterdam, Lisbon and Stockholm

p1_Cover-Dec11_EHDC-7 p06-07 29/11/2011 10:56 Page 1

Farbe/colour:PANTONE 288 CV

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 � le 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+� lm-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+� lm-coated+tablets/ (accessed September 2011). 10. Deacon CF. Diabetes Obes Metab 2011;13:7–18. 11. Blech S et al. Drug Metab Dispos 2010;38:667–678.

Prescribing Information (UK) TRAJENTA® 5 mg � lm-coated tablets 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 ef� cacy 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 bene� t of breast-feeding for the child and the bene� t 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 de� ned 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.

UK/TRJ/00091g Date of preparation: September 2011

Adverse events should be reported. Reporting forms andinformation can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone).

Control andcare matter

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

Efficacy – signifi cant HbA1c 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 fi rst one dose, once daily DPP-4 inhibitor excreted primarily via the bile:1,6–11 no dose adjustment required1

Prescribe – Trajenta® 5 mg once daily1

65813-10_BI_TRA_UK_evidentia_297-210_1.indd 1 22/09/2011 12:46

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

Combination therapy rids common infection from implanted medical devicesFungal infections

Obesity and Type 2 diabetes: What’s similar and what’s different?Reports from the EASD meeting, Lisbon

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

The rivalry between cisplatin and carboplatin goes on: BTOG 2 trialWorld Conference on Lung Cancer

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

Identification and management of breakthrough cancer pain remains a challengeReports from the EMCC, Stockholm

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

Considerably lower risk of stent thrombosis andrestenosis in 'new generation' drug-eluting stentsReporting from the ESC Congress, Paris

Environmental health risks of livestock farmingReports from the ERS Annual Congress, Amsterdam

EMA HighlightsEmerging uses of EMA approved drugs

The BIG FOURReporting from some of the latest journal articles

World Health MattersMedical news from around the world

FDA HighlightsEmerging uses of FDA-approved drugs

View from The Waiting RoomDying to live for ever

Bringing clinical evidence to practice in primary and secondary care

Contents

Volume 5 Issue 6 |

November/December 2011 |

ISSN 1753-464X

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

Emissions from livestockfarms cause greaterexacerbations in COPD and asthma patients

Aspirin halves hereditarycancer risk

Overweight children havethree times the risk of high blood pressure

Conference reports from: Amsterdam, Lisbon and Stockholm

COVER STORY

21 Overweight children have three times the risk of high blood pressure

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 3

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p3-Dec11_EHDC-7 p06-07 29/11/2011 10:34 Page 1

Guest editorial

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

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

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

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

by Dr. Sarah Jarvis

I

Statins and diabetes - More harm than good?

Editorial / Advisory Board:Omar Ali Bsc MRPhamS, Y Callan MD MRCGPM Gray MRPharmS, M Gupta MD MRCP Tim Lewis MD FRCP, K O’Neill Bsc MRCGP Mr Ian Pearce, C Weston MD MRCP

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

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4 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

ICRInternational Conference Reports

(UK) PUBLISHING

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

p4-5_Nov11_EHDC-7 p06-07 28/11/2011 14:56 Page 1

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 5

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.

References:

1. Scandinavian Simvastatin Survival Study Group.

Randomised trial of cholesterol lowering in 4,444

patients with coronary heart disease: the

Scandinavian Simvastatin Survival Study (4S). Lancet

1994; 344:1383–1389

2. Shepherd J, Cobbe SM, Ford I, et al, for the West of

Scotland Coronary Prevention Study Group.

Prevention of coronary heart disease with pravastatin

in men with hypercholesterolemia. N Engl J Med

1995; 333:1301-1307

3. Heart Protection Study Collaborative Group.

MRC/BHF Heart Protection Study of cholesterol

lowering with Simvastatin in 20,536 high-risk

individuals: a randomised placebo controlled trial.

Lancet 2002; 360: 7-22

4. Joint British Societies’ Guidelines on Prevention of

Cardiovascular Disease in Clinical Practice. Heart

2005; 91(Suppl): v1-v52

5. National Institute for Health and Clinical Excellence.

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

clinical guideline 87 London: NICE, 2009

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

11. Sattar N, Preiss D, Murray HM, et al. Statins and risk

of incident diabetes: a collaborative meta-analysis of

randomised statins trials. Lancet 2010; 375: 735-742

12. Taylor F, Ward K, Moore THM, et al. Statins for the

primary prevention of cardiovascular disease.

Cochrane Database Syst Rev 2011; 1(CD004816)

13. Cholesterol Treatment Trialists' (CTT) Collaboration.

Efficacy and safety of intensive LDL-cholesterol-

lowering therapy: A meta-analysis of data from 170

000 participants in 26 randomised trials. Lancet

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

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

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

diabetes with intensive-dose compared with

moderate-dose statin therapy. JAMA 2011; 305:

2556-2564

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p4-5_Nov11_EHDC-7 p06-07 28/11/2011 14:56 Page 2

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 Aspergillusfumigatus. "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 Oldfieldjim.oldfield@utoronto.caCOMPETING INTERESTS: The authors have declaredthat no competing interests exist.To see full report go tohttp://dx.plos.org/10.1371/journal.ppat.1002257

6 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

R

Fungal infections

Combination therapy rids commoninfection from implanted medical devices

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 albicans is the most common hospital-

acquired 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. albicanscan 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

of antifungal drugs, the echinocandins, targets

the enzyme that makes one of the two key sugar

polymers found in the cell wall, called beta-

glucan. 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

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 Udakisl.udakis@sgm.ac.uk

F

Fatal fungal infections resist newest class of drugs

p6-fungal-nov_EHDC-7 p06-07 28/11/2011 20:01 Page 1

Efficacy WHEN iT MaTTERS MOST

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

VFEND® (voriconazole)ABBREVIATED PRESCRIBING INFORMATION - UKPlease 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 fluconazole‑resistant 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

References1. 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

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

Anti-Infectives

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.

A

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

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

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 commonly-

encountered 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

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

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

IControversies in gestational diabetes

8 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

p8-9EASD-nov_EHDC-7 p06-07 28/11/2011 20:04 Page 1

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 DiabetesAtlas, 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 socio-

economic 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.

N

UN summit faces up to globaldiabetes epidemic

“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

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 9

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 andGynaecology. 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 cost-

effective treatments of diet and cheap oral

agents be used, there could be substantial

savings across the health system.

p8-9EASD-nov_EHDC-7 p06-07 28/11/2011 20:04 Page 2

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 11

Urology Reportby Samuel Peters

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 co-

authors 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 bygender and year. It also provides further statistics on theincreases expected by 2013.

Reference:Worldwide prevalence estimates of lower urinary tractsymptoms, overactive bladder, urinary. Irwin et al. BJUI. 108,pp1132 . (October 2011) doi:10.1111/j.1464-410X.2010.09993,10498.x

N

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

p11-OAB-nov_EHDC-7 p06-07 28/11/2011 15:42 Page 1

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 in-

versus out- patients, incidence of toxic

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

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

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 carboplatin-

based 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 al1

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

A

The rivalry between cisplatin andcarboplatin goes on: BTOG2 trial

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

12 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

DAY 8Gemcitabine1250mg/m2

DAY 8Gemcitabine1250mg/m2

DAY 8Gemcitabine1250mg/m2

DAY 1Gemcitabine 1250mg/m2 +

Cisplatin 80mg/m2

DAY 1Gemcitabine 1250mg/m2 +Carboplatin AUC6 (Wright)

RDAY 1

Gemcitabine 1250mg/m2 +Cisplatin 50mg/m2

p12-14_WCLC-nov_EHDC-7 p06-07 29/11/2011 10:42 Page 1

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 13

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 over-

expression 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).

A

Emerging immunotherapies in themanagement of lung cancer

p12-14_WCLC-nov_EHDC-7 p06-07 29/11/2011 10:42 Page 2

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, TTF-

1, CK7 are frequently used for adenocarcinoma

though Napsin A and mucin stains are most

specific but lack sensitivity. The histo-

pathological 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

of gefitinib as first-line systemic

treatment in exon 19 & 21

EGFR mutation positive

tumours was confirmed in the

iPASS trial. E4599 trial data

showed unprecedented extra

overall survival benefit of 3.9

months in bevacizumab

treated group (HR=0.69).

The latest excitement has been

the results of crizotinib, an

ALK-MET kinase inhibitor in

ALK positive tumours.

The genetics of squamous cell carcinoma

have not remained untouched. Some of the

significant genetic alterations already detected

like c-MET, p53 mutation, FGFR1 and DDR2 are

potential therapeutic targets. Peter

Hammerman presented a detailed genomic

analysis of squamous cell carcinoma of lung

tumours (n=118) at the Presidential Symposium

(PRS.1). Several other genes likely to be

important in the pathogenesis and

management of lung cancer are CMYC,

PDGFRA, EGFR, HER2, CCNV1 and PTEN.

Agents targeting the FGFR, PI3KCA and DDR

family are already

undergoing clinical

testing. The role of

thymidylate synthase

(TS), ERCC1 and RRM1

for selection of

platinum or non-

platinum doublets is

getting stronger.

Therefore, clinical

and histological

characteristics alone

should not be used for

treatment selection.

One must define the

tumours based on

genetic mutation,

deletion, amplification

and loss of

heterozygosity. This welcoming knowledge has

pushed us away from histology to molecular

biology and personalised therapy.

Unfortunately, this histological and molecular

profiling has to be based on small cytology and

small biopsy samples. Frequently these small

samples contain only a few undifferentiated

cells and so tumour subtype prediction

becomes difficult. Therefore, EGFR mutation

testing in plasma has been attempted and the

sensitivity reported has been variable and

proper validation of these techniques is

essential. We need to know the number, group

and “drivers” of genes critical for making the

treatment decision. How to account for the

differences between prognostic and predictive

markers? The precise target for some of the

targeted agents like bevacizumab and

cetuximab remains hazy. Better understanding

is essential to be able to translate these

advances from clinical trials into daily practice.

14 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

T

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

Table: Prevalence of genetic mutation

Squamous cell carcinoma Adenocarcinoma

KRAS mutation 5% 10-30%BRAF mutation 3% 2%EGFRMutation TK 2-5% 10-40%Amplification 30% 15%Mutation variant III 5% Rare

HER2Mutation TK Rare 2-4%Amplification 2% 6%

ALK (fusion) Rare 7%METMutation 5% 5%Amplification <10% <10%

P53 mutation 60-70% 50-70%LKB1 mutation 10-20% 3-40%PIK3CAMutation 2% 2%Amplification 33% 6%

Jean-Charles Soria WCLC 2011

Defining the unmet needs in NSCLC

Potential molecular targets

Unknown

KRAS

EGFR

HER2

MEK1

BRAF

ALK fusion

PIK3CA

ROS fusion

PDGFR

p12-14_WCLC-nov_EHDC-7 p06-07 29/11/2011 10:42 Page 3

LET’S THINK

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

BOEHRINGER INGELHEIM LTD, ELLESFIELD AVENUE, BRACKNELL, BERKSHIRE RG12 8YSTEL: +44 (0) 1344 424600 · FAX: +44 (0) 1344 741444 · WWW.BOEHRINGER-INGELHEIM.CO.UK

JOB NO: ONC0107 · DATE OF PREPARATION: MAY 2010

Evidentia A4_Layout 1 25/05/2010 09:53 Page 1

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.

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

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."

T

Chronic, non-cancer pain treatments aresub-optimal in most patients

Back painby Bruce Sylvester

16 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

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

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.

p16&18-Pain-nov_EHDC-7 p06-07 28/11/2011 15:07 Page 1

INTRODUCING A NEW CENTRALLY ACTING ANALGESIC1

Start to unlock severe chronic back pain with Palexia SR

Visit http://evi.palexia.co.uk for more information

Palexia SR (tapentadol prolonged release tablets) is indicated for the treatment of severe chronic pain in adults, which can be adequately managed only with opioid analgesics1

Tapentadol is a Controlled Drug, Schedule 2

back pain with Palexia SR

Visit http://evi.palexia.co.uk for more information

Palexia SR (tapentadol prolonged release tablets) is indicated for the treatment of severe chronic pain in adults, which can be adequately managed only with opioid analgesics1

Tapentadol is a Controlled Drug, Schedule 2

PALEXIA SR® and PALEXIA® Prescribing InformationRefer 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).

References1. Palexia SR, Summary of Product Characteristics.

February 2011

P11 0078ajDate of preparation: November 2011

3211 Ad 210x297Evid_v4a.indd 1 03/11/2011 17:53

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 toolleads to sub-optimal treatmentThe 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

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 onmedication optionsThe 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

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 requestmore knowledgeAlso, 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 wayA 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 nurse-

specific 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

A

Identification and management of breakthrough cancer pain remains a challenge

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

18 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

p16&18-Pain-nov_EHDC-7 p06-07 28/11/2011 20:10 Page 2

Abbreviated Prescribing Information - Amias® (candesartan cilexetil)(Refer to Summary of Product Characteristics before prescribing)Presentation: Tablets containing 2mg, 4mg, 8mg, 16mg or 32mgcandesartan cilexetil. Indication: Essential Hypertension in adults;Treatment of adult patients with heart failure and impaired left ventricularsystolic function (LVEF ≤ 40%) as add-on therapy to ACE-inhibitors orwhen ACE-inhibitors are not tolerated. Dosage: In hypertension: Startingand usual maintenance dose is 8mg od with or without food. Most of theantihypertensive effect is attained within 4 weeks. In some patients,whose blood pressure is not adequately controlled, the dose may beincreased to 16mg od and to a maximum of 32mg od. No doseadjustment is necessary in the elderly. A starting dose of 4mg isrecommended for patients with renal impairment (includinghaemodialysis), with mild to moderate hepatic impairment and those atrisk of hypotension due to intravascular volume depletion. In heart failure:Usual starting dose is 4mg od with or without food. Up-titration to thetarget dose of 32mg od or the highest tolerated dose is done by doublingthe dose at intervals of at least 2 weeks. No dose adjustment isnecessary for elderly patients or in patients with intravascular volumedepletion, renal impairment or mild to moderate hepatic impairment.Amias can be administered with other heart failure treatment includingACE-inhibitors, beta-blockers, diuretics and digitalis or a combination ofthese. The combination of an ACE inhibitor, a potassium-sparing diuretic(e.g. spironolactone) and Amias is not recommended and should beconsidered only after careful evaluation of the potential benefits and risks.Safety and efficacy of Amias not established in children. Contra-indications: Hypersensitivity to any component of Amias. Second andthird trimesters of pregnancy. Severe hepatic impairment and/or

cholestasis. Warnings and Precautions: Monitoring of serumpotassium and creatinine levels is recommended during dose titration ofAmias in patients with heart failure and regularly in patients takingconcomitant ACE-inhibitors and potassium sparing diuretics such asspironolactone. Periodic assessments of renal function is alsorecommended especially in elderly heart failure patients ≥ 75 years andin heart failure patients with impaired renal function. Hypotension mayoccur during treatment with Amias in heart failure patients. Risk ofincreased blood urea and serum creatinine in patients with renal arterystenosis. Periodic monitoring of serum potassium and creatinine levels isrecommended in patients with renal impairment. Amias should becarefully titrated with thorough monitoring of blood pressure in patientson haemodialysis. Caution should be observed when initiating therapyand correction of hypovolemia should be attempted. Possiblehypotension during anaesthesia and surgery. Not recommended inpatients with primary hyperaldosteronism. As with other vasodilators,use with caution in patients with aortic and/or mitral valve stenosis orobstructive hypertrophic cardiomyopathy. Amias should not be initiatedduring pregnancy. When pregnancy is confirmed, treatment with Amiasshould be stopped immediately, and, if appropriate, alternative therapycommenced. 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 otherantihypertensives. Use with lithium is not recommended. If thecombination proves necessary, careful monitoring of serum lithium levelsis 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 withthe overall incidence similar to placebo. Overall incidence showed noassociation with dose or age. Adverse events commonly seen in clinicaltrials and postmarketing include: respiratory infection, dizziness/vertigoand 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, renalimpairment/failure, cough, decreased haemoglobin and increasedcreatinine and urea. In heart failure clinical trials (e.g. CHARM), theadverse event profile of Amias was consistent with the pharmacology ofthe drug and health status of the patients. In the CHARM clinicalprogramme, 21% of the Amias group and 16.1% of the placebo groupdiscontinued treatment due to adverse events. Adverse reactionscommonly seen in clinical trials and postmarketing were: hyperkalaemia,hypotension and renal impairment/failure. Adverse reactions seen veryrarely include leukopenia, neutropenia, agranulocytosis, hyponatraemia,dizziness, headache, cough, nausea, increased liver enzymes, abnormalhepatic function or hepatitis, angioedema, rash, urticaria, pruritis, back pain, arthralgia and myalgia. Legal Category: POM. Packs andBasic 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 AuthorisationHolder: Takeda UK Ltd., Takeda House, Mercury Park, Wycombe Lane,

Wooburn Green, High Wycombe, BUCKS HP10 0HH. For furtherinformation contact the Marketing Authorisation Holder:Telephone: 01628 537900, Fax: 01628 526615. ®Registered trademarkowned 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 eventsshould 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. Eklind-Cervenka M et al. JAMA 2011; 305(2): 175-82. 4. Young JB et al.Circulation 2004; 110: 2618-2626. 5. Takeda UK Ltd. Amias (candesartancilexetil) Summary of Product Characteristics. www.medicines.org.uk.

† Reduced risk of cardiovascular disease, morbidity, mortality andelective coronary revascularisation. ‡ Amias is the only ARB licensed forheart failure that can be prescribed as an alternative in patients intolerantto ACE-inhibitors, or in addition to an ACE-inhibitor with/without a beta-blocker in patients with LVEF ≤40%.

Code: TA110579dDate of preparation: May 2011

Respect is earnedWith its superior BP reductions,1 reduced CV risk†2 and increasedCHF 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

Less than

12 months

until patent expiry

www.heartzone.co.uk

AMI378 Clin Pharm-BJ Gen 297x210 aw 24/05/2011 12:30 Page 1

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 theCanadian Institutes of Health Research, theOntario Ministry of Health and Long-Term Careand the Canadian Stroke Network.

Contact: Kathy Wallis

For further information on the study please

contact kwallis3@uwo.ca

R

Stroke prevention clinics reduce one-yearmortality rates by over 25%

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,

smoking, low exercise capacity and high blood

pressure - also concern us after a TIA," said

Neville Suskin, M.B.Ch.B., M.Sc., senior

investigator of the study. "We know that cardiac

rehab addresses these risk factors in patients

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

outpatient cardiac rehab programme

for approximately 7½ months and then

were re-assessed for risk factors.

Researchers assessed the effectiveness

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

completed the rehab process.

C

Cardiac rehabilitation programmes benefitpatients after mini or mild stroke

Cardiology Reportsby Bruce Sylvester

20 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

"Many of the risk factors that we

worry about after a heart attack ...

also concern us after a TIA."

Dr. Neville Suskin

Two Canadian studies have emphasised the importance of stroke prevention clinics and cardiac rehabillitation programmes

p20-21_Cardio-nov_EHDC-7 p06-07 28/11/2011 15:20 Page 1

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 21

HILDREN WHO ARE overweight

or obese children have a three-

fold 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.

C

Overweight or obese children have atripled risk of high blood pressure

"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.

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

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.

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

p20-21_Cardio-nov_EHDC-7 p06-07 28/11/2011 15:20 Page 2

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 drug-

eluting 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 Internet-

based, with recording of data online through

an Internet interface in the catheterisation

laboratory; data are transferred in an

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 population-

including 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

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.

22 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

R

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

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

A report from the nationwide complete Swedish Coronary Angiography and Angioplasty Registry (SCAAR)

p22_ESC-stent-Nov_EHDC-7 p06-07 28/11/2011 15:52 Page 1

Press release

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 23

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

IMI winners of 2011 eHealthcareLeadership AwardsRecognised at Healthcare Internet Conference in Orlando

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 emailpeter@medicalimi.com

I

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

p23-press release_Nov11_EHDC-7 p06-07 28/11/2011 15:55 Page 1

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 allergy-

related, 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 animalfarms affect the airways of neighbouring residents?Session: Oral Presentation : Outdoor air pollution studies.

E

Environmental health risks of livestock farming

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

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

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 ofadult-onset asthma. Session: Poster Discussion :Genetical and environmental risk factors forrespiratory diseases.

T

Alcohol can reduce asthma risk

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

24 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

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

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

p24-26_Respir-nov_EHDC-7 p06-07 28/11/2011 20:12 Page 1

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 25

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 double-

blind, parallel group trial, compared the efficacy

and safety of flutiform® with the

budesonide/formoterol combination in 261

adolescents and adults with moderate-to-

severe, 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 post-

dose 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 double-

blind, 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 widely-

used 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 vsbudesonide/formoterol for the treatment of asthma:a non-inferiority trial. Abstract presented at ERS, 24-28.09 2011 in Amsterdam, Netherlands

2. Bodzenta-Lukaszyk A, et al. Fluticasone propionate/formoterol fumarate combination therapy hascomparable efficacy to its individual componentsadministered concurrently. Abstract presented atERS, 24-28.09 2011 in Amsterdam, Netherlands

3. Pearlman DS, et al. Fluticasone propionate/formoterol fumarate combination therapy hassuperior efficacy to both fluticasone and formoterolalone. Abstract presented at ERS, 24-28.09 2011 inAmsterdam, Netherlands .

4. Global Initiative for Asthma (GINA). Global burden ofasthma report. 2004. Available at:http://www.ginasthma.com/ReportItem.asp?l1=2&l2=2&intId=94. Accessed on 22 August 2011

5. Masoli M, et al. The global burden of asthma:executive summary of the GINA DisseminationCommittee report. Allergy 2004 May;59(5):469-78

6. Braman SS. The global burden of asthma. Chest2006;130(1 Suppl):4S-12S

7. Global Initiative for Asthma (GINA). Global strategyfor asthma management and prevention. 2010.Available at: http://www.ginasthma.org/guidelines-gina-report-global-strategy-for-asthma.html.Accessed on 22 August 2011

8. Bodzenta-Lukaszyk A, et al. Efficacy and safety offluticasone and formoterol in a single pressurizedmetered dose inhaler: Respiratory Medicine. 2011;105:5, 674-682

9. Bodzenta-Lukaszyk A, et al. Fluticasonepropionate/formoterol fumarate combinationtherapy is as effective as fluticasonepropionate/salmeterol xinafoate, but has a morerapid onset of action in the treatment of asthma.BMC Pulm Med. 2011. doi:1471-2466/11/28

T

New data show good efficacy and safetyfor combination in asthma patients

p24-26_Respir-nov_EHDC-7 p06-07 28/11/2011 20:12 Page 2

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

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.

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 isassociated with increased risk of asthma hospitalisation.Session: Thematic Poster Session : Respiratoryepidemiology: quality of life, therapy andsocioeconomics

A

HRT appears to increase risk of hospitalisationfrom severe asthma attacks

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

26 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

Women taking postmenopausal hormone replacement therapy (HRT) may have an increased risk of severe asthmaattacks requiring hospitalisation, scientists warn

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.

Journal and Literature Reviews Local and International News

Case Studies Web Links Conference Reviews

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.

is a FREE request only e-journal for healthcareprofessionals delivered to you by email

p24-26_Respir-nov_EHDC-7 p06-07 28/11/2011 20:12 Page 3

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 smallbusinesses

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 approvedThe 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

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 27

by Gary Finnegan

TEuropean Parliament U-turn on EMA budget

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.

European Medicines Agency

highlights

p27_EMA_nov11_EHDC-7 p06-07 28/11/2011 20:14 Page 1

28 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

Journal reviews

www.nejm.org

Medical management could bebest for stroke prevention:SAMMPRIS study

PATIENTS 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

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.

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 longer-

term 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

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 lungcancer deaths

A 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%.

by Bruce Sylvester

Reporting from someof the latest articles in

"At this time, stenting cannot besupported in routine practice;however, whether subgroupsmay benefit from this or other

interventions in the futureneeds further study."

p28-29_Big4_Nov_EHDC-7 p06-07 28/11/2011 15:59 Page 1

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.

www.bmj.org

Some contraceptive pills appearto raise blood clot risk

ARETROSPECTIVE 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 three-

fold, 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.

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

R ESEARCHERS REPORTED in The Lanceton 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

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.”

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 29

When compared with

non-users of hormonal

contraception, pills with

levonorgestrel increased the

risk of VTE three-fold...

This suggests that that

aspirin might be causing

these cells to destruct before

they turn cancerous.

BMJ

p28-29_Big4_Nov_EHDC-7 p06-07 28/11/2011 15:59 Page 2

30 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

Medical news from around the world

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.

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

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 CanadianMedical 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 halvedthanks 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

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 hospital-

based 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

by Gary Finnegan

World Health Matters

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.

p30-31_Nov11_EHDC-7 p06-07 28/11/2011 16:00 Page 1

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 facility-

based strategy on neonatal mortality is much

greater than that reported for community-

based 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 diabetesdetection 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 Orešic from the

VTT Technical Research Centre of Finland

suggests that autoimmune diabetes is

preceded by a reduction in gut microbial

diversity of the Clostridium leptum subgroup,

elevated plasma leptin and enhanced glucose-

stimulated 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 PLoSComputational 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 leptumsubgroup 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 ofICD patientsA 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 in-

clinic 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.

“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.”

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 31

Translation: doctors could

potentially use changes in

bacteria levels in the gut as

an early warning system

for diabetes.

“Currently, regular in-clinic

follow-up must be performed

every three months, according

to manufacturer guidelines.”

p30-31_Nov11_EHDC-7 p06-07 28/11/2011 16:00 Page 2

32 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

FDA highlights

Atypical antipsychotics effectivefor only a few off-label uses

IN 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.

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 off-

label 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-

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.

"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 catheterinfections 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 SocietyNephrology (JASN).

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.

by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs

"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. “

“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...”

p32-33_FDA_Nov_EHDC-7 p06-07 28/11/2011 16:03 Page 1

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.

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

Z 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 inchronic lymphocytic leukaemia

COMPARED 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.

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 progression-

free 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.

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 33

Half of subjects had catheter

locks containing the novel

combination and the other

half had catheter locks

containing only heparin.

“Unlike common regimens

used to treat CLL, the new

two-drug combination

spares patients from the

toxicities of additional

alkylating drugs.”

p32-33_FDA_Nov_EHDC-7 p06-07 28/11/2011 16:03 Page 2

34 EV IDENT IA • VOLUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011

View from the waiting room

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. 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 Anti-

Aging 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

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

by Steve Devrell

ADying to live for ever

Is immortality a work of fiction

and religion, or is it an achievable

goal? Well it depends very much on

who you listen to.

p34-35_WR_Nov11_EHDC-7 p06-07 28/11/2011 20:16 Page 1

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?

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!

EV IDENT IA • VO LUME 5 • I SSUE 6 • NOVEMBER /DECEMBER 2011 35

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?

p34-35_WR_Nov11_EHDC-7 p06-07 28/11/2011 20:16 Page 2

feel?Tell me Nathan,

how does FOSTAIR

FOSTAIR® (beclometasone dipropionate and formoterol fumarate dihydrate) pressurised inhalation solutionPrescribing 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.

REFERENCES1. 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.

Now licensed for use with

AeroChamber PlusTM

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.

10090FOS Evid Nathan 297x210.indd 1 04/02/2011 13:49