Evidentia October 2011

Volume 5 Issue 5 | October 2011 | ISSN 1753-464X

Environmental toxins seriously effect endocrine system.

EMA gives go ahead for first paediatric-use only medicine ESC gives public message to Parisians Prevention of lifestyle diseases discussed in high level UN meeting

Conference reports from: Chicago, Paris and San Diego

The first and only orodispersible tablet for erectile dysfunction (ED)1,2

Ready when they are

Introducing Levitra® orodispersible tablet – the first and only treatment for ED to dissolve on the tongue within seconds;3 comes in a discreet, pocket-friendly pack to meet the needs of today’s man.

ED therapy wherever he needs it Levitra® film-coated tablets and Levitra® orodispersible tablets (vardenafil) Prescribing Information (Refer to full Summary of product Characteristics (SmPC) before prescribing) Presentation: Levitra® film-coated tablets: 5/10/20mg vardenafil (as hydrochloride). Levitra® orodispersible tablets: 10mg vardenafil (as hydrochloride). Indication: Treatment of erectile dysfunction. To be effective, sexual stimulation is required. Posology and method of administration: Film-coated: 10mg approximately 25–60 minutes before sexual activity. Based on efficacy and tolerability, dose may be increased to 20mg or decreased to 5mg. Maximum dose is 20mg/day. Can be taken with or without food. Onset of activity may be delayed if taken with a high fat meal. Orodispersible: 10mg approximately 60 minutes before sexual activity. Maximum dose is 10mg/day. Can be taken with or without food, but not with liquid.

Elderly men (>65 years): no dose adjustment required, though increase to a maximum 20mg film-coated tablets dose should be carefully considered depending on individual tolerability. Hepatic and renal impairment: Consider starting with 5mg film-coated tablets in patients with mild-moderate hepatic impairment or severe renal impairment. Max dose in patients with moderate hepatic impairment is 10mg film-coated tablets. Orodispersible tablets should not be used in patients with moderate to severe hepatic impairment or with end-stage renal failure. Paediatrics: not indicated for individuals <18 years of age. Use with other medicinal products: In combination with moderate CYP3A4 inhibitors, the dose should not exceed 5mg film-coated tablets. Contra-indications: Hypersensitivity to vardenafil or to any excipients; coadministration with nitrates/nitric oxide donors (such as amyl nitrite); loss of vision in one eye due to NAION; men for whom sexual activity is inadvisable; severe hepatic impairment; end-stage renal disease requiring dialysis; hypotension (BP <90/50 mmHg); recent stroke or myocardial infarction (≤6 months); unstable angina; known hereditary retinal degenerative disorders; concomitant use of potent CYP3A4 inhibitors ketoconazole and itraconazole (oral form) in men older than 75 years; concomitant use of potent HIV protease

inhibitors. Warnings and Precautions: Given cardiac risk associated with sexual activity, consider cardiovascular status. Vardenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. Patients with left ventricular outflow obstruction can be sensitive to the actions of PDE5 inhibitors. Use with caution in patients with anatomical deformation of the penis or conditions which predispose to priapism. Combination with other treatments for erectile dysfunction, including Levitra® orodispersible tablets, is not recommended. Concomitant use of alpha-blocker therapy may lead to symptomatic hypotension, consider only if therapy is stable, initiate vardenafil at a starting dose of 5mg film-coated tablets and consider a time separation of dosing. Concomitant use with potent CYP3A4 inhibitors should be avoided. Dose adjustment might be necessary when given concomitantly with moderate CYP3A4 inhibitors, e.g. erythromycin or clarithromycin.

Avoid grapefruit or grapefruit juice. Prolongation of QTc interval avoid use in patients with relevant risk factors. In case of sudden visual defect, treatment should be stopped. Administration to patients with bleeding disorders or active peptic ulceration should be considered carefully. Orodispersible tablets contain aspartame and sorbitol. Interactions: CYP3A4 inhibitors may reduce vardenafil clearance. Nicorandil may have a serious interaction with vardenafil due to the nitrate component. Prescribers should consult the SmPCs for full details on interactions. Pregnancy and lactation: not indicated for use in women; no fertility data available. Effects on ability to drive and use machines: Patients should be aware of how they react to Levitra® before driving or operating machinery.

Undesirable Effects: Very common: Headache. Common: flushing, dizziness, nasal congestion, and dyspepsia. Serious side effects: cf. CI/Warnings and Precautions - in addition: ventricular tachyarrythmias, chest pain, angina pectoris, myocardial infarction, gastritis, seizure, somnolence, syncope, amnesia, paraesthesia/ dysaesthesia, priapism, NAION, visual defects, increased intraocular pressure, sudden deafness, allergic reaction, allergic oedema and angioedema. Incidence of ADRs (especially “dizziness”)

slightly higher in patients with history of hypertension. Serious cardiovascular events, including cerebrovascular haemorrhage, sudden cardiac death, transient ischaemic attack, unstable angina and ventricular arrhythmia reported post-marketing in temporal association with another medicinal product in the same class.

Prescribers should consult the SmPC in relation to other side effects. Overdose: Doses of 40mg twice daily have been associated with severe back pain without any muscle or neurological toxicity.

Standard supportive measures should be adopted. Renal dialysis is not expected to accelerate clearance. Legal Category: POM. Package Quantities and Basic NHS Costs: Film-coated: 4 x 5mg (£7.56), 8 x 5mg (£15.12), 4 x 10mg (£14.08), 8 x 10mg (£28.16), 4 x 20mg (£23.48), and 8 x 20mg (£46.96). Orodispersible: 4 x 10mg (£17.88). MA Number(s): EU/1/03/248/001-015. Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom, Telephone: 01635 563000. Date of revision: June 2011.

Levitra® is a registered trademark of Bayer AG.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard. gov.uk. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk References: 1. Sperling H, Debruyne F, Boermans A, et al. J Sex Med 2010;7:1497–1507.

2. Levitra® ODT Summary of Product Characteristics.

3. Heinig R, Weimann B, Dietrich H, et al. Clin Drug Investig 2011;31(1):27–41.

UK.PH.GM.LVT.310h

Date of preparation: August 2011

Bringing clinical evidence to practice in primary and secondary care

Contents COVER STORY

4

Guest Editorial by Riyaz Shah

6

Sexual medicine study

8

Volume 5 Issue 5 | October 2011 |

Thoracic oncology update ASCO 2011

ISSN 1753-464X

Environmental toxins seriously effect endocrine system.

When erectile dysfunction isn't the whole story

Gangrene expert talks about the proper approach in diabetic patients

EMA gives go ahead for first paediatric-use only medicine

Reports from American Diabetes Association Scientific Sessions, San Diego

ESC gives public message to Parisians Prevention of lifestyle diseases discussed in high level UN meeting

Conference reports from: Chicago, Paris and San Diego

12

Progress in lung cancer clinical research

16

ESC Congress 2011 highlights

19

EMA Highlights

20

The BIG FOUR

22

World Health Matters

24

FDA Highlights Emerging uses of FDA-approved drugs

26

Aspirin - the wonder drug

11 Environmental toxins ‘might

Reports from American Society of Clinical Oncology, Chicago

be wreaking havoc on the body’s endocrine system’ Reporting from the European Society of Cardiology Congress, Paris

8

Emerging uses of EMA approved drugs

Reporting from some of the latest journal articles

23

Medical news from around the world

24

View from The Waiting Room

27

E V I D E N T I A • V O L U M E 5 • I S S U E 5 • O C TO B E R 2 0 1 1

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Guest editorial

by Dr. Riyaz Shah, Consultant Medical Oncologist, Kent Oncology Centre

Thoracic oncology update ASCO 2011

T

he ASCO 2011 Annual Meeting took place in early June at the vast McCormick Place Convention Centre in Chicago. With 337 original peer reviewed abstracts relating to lung cancer, a full summary is beyond the scope of this update but I will attempt to highlight some key studies.

0.05) in favour of erlotinib.

A total of 1227 patients were screened and 174 randomised (86 in erlotinib arm and 88 in chemotherapy arm). Baseline characteristics were well balanced. 66-72% of patients were never smokers and 2/3 of patients harboured an exon 19 deletion.

EGFR Mutation (mutEGFR) positive lung cancer To date several randomised Phase III clinical trials have established the role of EGFR tyrosine kinase inhibitors in treating EGFR activating mutation positive lung cancer in the first-line setting. These trials randomised patients to either conventional cytotoxic chemotherapy or EGFR tyrosine kinase inhibitors (TKI). Most trials looked at gefitinib but a single trial evaluated erlotinib. The efficacy outcomes for these trials were similar and all were performed in Asian patients.

Rosell et al presented early results from the EURTAC trial. This trial was performed by Spanish, Italian and French groups and represents the first randomised Phase III trial to look at the question of efficacy of EGFR TKIs in Caucasian mutEGFR patients. Chemonaïve, stage IIIB/IV patients with a PS of 0-2 were tested for EGFR mutations using laser capture microdissection followed by both DNA sequencing and ARMS PCR. Patients with either an exon 19 deletion or exon 21 L858R mutation were randomised to either 4 cycles of conventional platinum based chemotherapy or 150mg erlotinib once a day. The primary endpoint was PFS and the study was powered to detect a HR of 0.6 (80% power and alpha =

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

While OS data was still immature, many patients in the chemo arm crossed over to erlotinib. As expected there was no OS benefit and is consistent with the other published studies.

Results showed a PFS benefit for erlotinib.

Median PFS was 5.2 months in the chemotherapy arm and 9.7 months for erlotinib (HR 0.37 [0.25-0.54]; p=<0.0001).

The response rate to erlotinib was 58%. While results were consistent with the other published trials, chemotherapy resulted in a response rate of only 15%, which seems low and unexplained.

While OS data was still immature, many patients in the chemo arm crossed over to erlotinib. As expected there was no OS benefit and is consistent with the other published studies.

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

ICR (UK) PUBLISHING

International Conference Reports

The authors rightly concluded that this was the first randomised trial to confirm the benefit of EGFR TKI as first-line therapy in Caucasian patients with EGFR activating mutations.

Currently NICE guidelines approve first-line gefitinib use in EGFR mutation positive lung cancer. No doubt this data will facilitate licensing of erlotinib in the same setting.

Unfortunately not all MDMs in the UK are routinely testing patients for EGFR mutations.

Given the body of evidence showing efficacy and quality of life benefits for TKI therapy, this position seems increasingly unsustainable.

Updated results from 2 key trials of EGFR TKI vs. chemotherapy in mutEGFR patients were also presented. Quality of life benefits of erlotinib over chemotherapy were seen in OPTIMAL while no survival benefit was seen in NEJ002; a trial of gefitinib vs. chemotherapy in mutEGFR. Data were presented on a new EGFR TKI called icotininb showing comparable activity to the established drugs.

Other mutations in NSCLC One of the most exciting developments in lung cancer therapeutics has been the realisation that the disease which we treated as a single entity not that long ago is in fact a multitude of different conditions. We already have histologically directed treatment with non-squamous tumours benefitting from pemetrexed based regimens. In addition we already know about EGFR mutations and ALK translocations.

An exciting piece of work presented at ASCO this year was a genotyping project led

by Dr. Paul Bunn of Denver Colorado. He

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© ICR-UK Limited. The information contained in Evidentia is intended to be used with professional medical knowledge and in conjunction with other sources of clinical evidence and product literature.

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

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implied a potential benefit in larger T2 tumours with a significant HR for tumours >7cm in size (HR .052, p=0.048). This remains an untested hypothesis but many oncologists will consider recommending adjuvant chemotherapy after resection of large T2 tumours.

founded the ‘Lung Cancer Mutation Consortium’, a collaboration of 14 academic centres in the US with the aim of testing a panel of lung adenocarcinomas for known driver mutations. They tested tumour tissue in over 1000 patients with stage IV lung adenocarcinoma and presented preliminary data from the first 516 cases. A panel of 10 specific genetic abnormalities was selected due to their known potential as drug targets (EGFR, KRAS, BRAF, Her-2, PIK3CA, AKT, NRAS, MEK1, EML4-ALK and Met amplification). Results showed that 54% of lung adenocarcinomas had one of these mutations and interestingly almost all (97%) were mutually exclusive. This raises the tantalizing prospect of individualized molecularly directed therapeutics in the future. Naturally these agents will all need to be prospectively validated in clinical trials before establishing their role in routine care.

One of the most exciting developments in lung cancer therapeutics has been the realisation that the disease which we treated as a single entity not that long ago is in fact a multitude of different conditions.

associated with more frequent dose reduction and resultant lower relative dose intensity. No difference in median OS was seen (7.5 vs. 7.8 months). Amrubicin was associated with a greater response rate (31% vs. 17%), longer duration of response, longer PFS and improvements in appetite, cough and dyspnoea. Topotecan was associated with more myelosuppression and no symptom improvements on the Lung Cancer Symptom Scale. Essentially amrubicin is an active drug in this disease and the oncological community will welcome another therapeutic option however, CAV will probably remain the mainstay of second-line therapy in refractory SCLC.

Mesothelioma Little new data other than the results of a European study showing switch maintenance with thalidomide is not effective.

Summary Adjuvant chemotherapy CALGB9633 was a pivotal trial in early stage lung cancer. In this trial 344 pts with stage IB NSCLC who had undergone curative resection were randomised to observation or 4 cycles of adjuvant carboplatin + paclitaxel. In 2004 the safety monitoring board stopped the study due to a signal of efficacy. This was presented as an ASCO oral in 2004. (The hazard ratio for survival was significant at 0.62). A subsequent oral ASCO presentation in 2006 showed this benefit had disappeared. This year updated results

Small cell lung cancer Jotte et al presented the data from the ACT-1 trial, which randomised patients with small cell lung cancer in the second-line setting to either amrubicin or iv topotecan. Amrubicin is a potent topoisomerase II inhibitor that already has approval in Japan. The primary endpoint was survival. Over 600 pts were randomised in this trial. Both arms were well balanced. While the median number of cycles given was the same (4) in both arms, topotecan was

This was yet another bumper ASCO for lung cancer. So much that has not been touched in this brief synopsis. The key message revolves around the expanding understanding of molecular abnormalities, biomarkers and targeted therapies. There is no doubt that the face of cancer therapeutics is changing rapidly and the UK is in danger of falling behind without increased support for pathology labs and oncology units. However, prevention and early detection remains the strategies likely to save the most lives.

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E V I D E N T I A • V O L U M E 5 • I S S U E 5 • O C TO B E R 2 0 1 1

5

Sexual medicine study

When erectile dysfunction isn't the whole story 65% of men with ED are unable to have an orgasm, and 58% have problems with ejaculation, according to NewYork-Presbyterian/Weill Cornell study

F

OR MEN WITH erectile dysfunction (ED), 65% are unable to have an orgasm and 58% have problems with ejaculation, according to new research led by physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Centre.

The study followed 12,130 men with mild to severe ED and is the largest-ever analysis of orgasmic and ejaculatory dysfunction. Results are published in the British Journal of Urology International.

Approximately 30 million American men, or half of all men aged 40 to 70, have trouble achieving or sustaining an erection. "While medications have been successful in helping many of these men, our research suggests there are other common sexual issues that remain largely unaddressed," says Dr. Darius Paduch, the study's lead author; male sexual medicine specialist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center; and assistant professor of urology and reproductive medicine at Weill Cornell Medical College.

"We must expand the definition of quality of life when it comes to sexual performance," Dr. Paduch adds. "For the last few decades, we have focused on penile rigidity, with erection as a

6

synonym of normal sexual function. However, many patients say that problems with ejaculation - like decreased force or volume or decreased sensation of orgasm - are just as critical.

"Despite the frequency of these issues, nonerectile sexual dysfunction is underreported and undertreated due to social stigma and misunderstandings about the physiology of male sexual response and orgasmic dysfunction in particular. For decades it was believed that only women had problems with orgasm; our study shows that orgasmic dysfunction could be as prevalent among men as it is among women."

While severity of dysfunctional ejaculation and orgasm correlated with ED severity, says Dr. Paduch, these issues were still surprisingly common in men with very mild ED: Orgasm dysfunction was reported by 26% in this group, and ejaculation dysfunction by 18%. "This suggests that non-erectile sexual dysfunction is a regular occurrence even in men without ED." The study reported factors associated with increased risk of ejaculatory and orgasmic dysfunction which includes commonly prescribed antidepressant medications.

Ejaculatory and orgasmic dysfunction can be caused by low testosterone and minor brain

E V I D E N T I A • V O L U M E 5 • I S S U E 5 • O C TO B E R 2 0 1 1

injury such as that sustained by motor vehicle accident victims, football players suffering from concussion, or by soldiers with combat-related blast head injuries.

“For decades it was believed that only women had problems with orgasm; our study shows that orgasmic dysfunction could be as prevalent among men as it is among women."

The most common ejaculatory dysfunction is premature ejaculation, but the condition also describes delayed ejaculation, inability to ejaculate, painful ejaculation, retrograde ejaculation, as well as a reduced volume of ejaculate or diminished force of ejaculation.

Orgasm dysfunction is defined as absence of an orgasm.

Going forward, Dr. Paduch and Dr. Bolyakov will use uniquely specialised equipment available in their lab at Weill Cornell to measure biological and subjective changes that occur in men during orgasm and ejaculation.

They will look at whether testosteronereplacement therapy can help men who suffer from non-erectile sexual dysfunction.

"Sexual satisfaction is known to be linked to the likelihood of orgasm, which in turn affects emotional intimacy and relationship satisfaction.

The high prevalence of both orgasmic and ejaculatory dysfunction warrants further clinical and translational research into new treatments to improve sexual health and overall quality of life for hundreds of thousands of affected men and their loved ones," says Dr. Paduch.

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

Efficacy – significant HbA

1c

reductions versus placebo2–4

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

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

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

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

Prescribe – Trajenta

®

1,6–11

1

5 mg once daily1

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

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

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

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

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

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

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

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

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

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

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

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

American Diabetes Association Reports from ADA Scientific Sessions, San Diego by Thomas R. Collins

Gangrene expert talks about the proper approach in diabetic patients

D

IABETES-INDUCED gangrene is a “menace” to both doctors and patients, but can be controlled through aggressive treatment with a multidisciplinary medical team to prevent its onset, an expert on the topic said at the 2011 American Diabetes Association Scientific Sessions.

Robert Frykberg, MD, Chief of the Podiatry Section of the Phoenix VA Healthcare System, said diabetes with complications is “maliganant diabetes,” bringing high mortality rates within five years - and a major problem among them is gangrene.

“It’s important for us to recognise the underlying pathophysiologic perturbations that are so prevalent in these patients that we all deal with.”

Dr. Robert Frykberg

“It’s important for us to recognise the underlying pathophysiologic perturbations that are so prevalent in these patients that we all deal with,” Dr. Frykberg said in the Roger Pecoraro Lecture, named in honor of the doctor who was a pioneer in the amputation prevention field. “If we understand this we can treat these people much more effectively.”

Amputation among diabetes patients and complications that lead to amputation, rank among the worst complications a diabetes patient can have.

Studies have found that peripheral artery disease brings with it a 32% five-year mortality rate; Charcot foot, a sudden softening of bones

8

and tissues in the lower extremities, a 41% rate; foot ulcers, a 44% rate; and amputation itself, a 68% rate, Dr. Frykberg said.

A study on amputation found that, for below-the-knee amputation, the one-year survival rate was 74.5% and the five-year rate 37.8%. The situation is considerably worse for above-the-knee amputations, with a oneyear survival rate of just 50.6% and a fiveyear rate of 22.5%.

As Dr. Frykberg noted: “This is just one amputation - how many of our patients have bilateral major amputations?”

Diabetes, with its onset of vascular disease and neuropathy, brings about a milieu of conditions that all work together to set the stage for foot ulcerations and possible amputation - and it’s important for doctors to understand these underlying factors to help treat their patients, he said.

It’s been found that faulty wound healing contributes to 81% of diabetic limb amputations; ulceration, 84%; and minor trauma, 81%.1 Dr. Frykberg said, though, that there is hope to be found in what a colleague of his calls the “stairway to amputation” - a clearly defined series of steps leading to amputation: First is neuropathy, with or without peripheral artery disease. Then comes some injury, possibly a burn, then a wound, then infection, then gangrene.

“The important thing about this ‘stairway to amputation’ is that it presents many possible levels to intervene and thereby prevent gangrene and subsequent amputation,” Dr. Frykberg said. “And we need to be able to focus on these areas of possible intervention if we’re going to be effective in saving diabetic limbs.”

The proper way to go about prevention of gangrene and amputation is to treat patients with a multi-disciplinary team in which the podiatrist, diabetologist, vascular surgeon and ancillary services such as radiology all

E V I D E N T I A • V O L U M E 5 • I S S U E 5 • O C TO B E R 2 0 1 1

work together with the patient.

“A multi-disciplinary team is absolutely essential,” he said. “Through the multidisciplinary team we can optimise our medical management of the various co-morbidities,” treating infection early and aggressively, treating ischaemia optimally, doing footsparing surgery when appropriate, doing proper wound care, and overseeing prevention programmes.

It’s an approach that has been proven to work, he said, pointing to his own Phoenix VA Healthcare System, where the diabetic amputation rate dropped from nearly 12 per 1,000 patients in 2000 to fewer than 3 per 1,000 in 2010.

“We’ve seen from the year 2000 a dramatic decrease in the amputation rate of diabetic patients,” Dr. Frykberg said. “The multi-disciplinary approach works and we should all be practicing this very diligently.”

References: 1. Pecoraro R, Reiber G, Burgess E. Diabetes Care 1990; 13(5): 513-521

STROKE PREVENTION The first new oral anticoagulant for stroke prevention in atrial fibrillation in 50 years Pradaxa® 150mg b.d.: more effective stroke prevention vs warfarin is now available for adult patients with nonvalvular atrial fibrillation plus one or more risk factors.1,2 Compared to warfarin, Pradaxa® 150mg b.d. provides: • 35% reduced relative risk of stroke or systemic embolism (p=0.0001, ARR†3 per year 0.60%)1

• Similar rates of major bleeding4,5 • 59% reduced relative risk of potentially devastating intracranial bleeding (p<0.001, ARR†3 per year 0.44%).4,5

It’s time for Pradaxa® 150mg b.d.

Prescribing information can be found overleaf

American Diabetes Association

by Thomas R. Collins

Prescribing Information (SPAF – UK) PRADAXA®ź (dabigatran etexilate) Capsules containing 110 mg or 150 mg dabigatran etexilate (as mesilate) Action: Direct thrombin inhibitor Indication: Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors: Previous stroke, transient ischemic attack, or systemic embolism (SEE); Left ventricular ejection fraction < 40 %; Symptomatic heart failure, ≥ New York Heart Association (NYHA) Class 2; Age ≥ 75 years; Age ≥ 65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension Dose and Administration: Recommended daily dose 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term. In case of intolerability to dabigatran, patients should be instructed to immediately consult their doctor.

Elderly: Aged ≥ 80 years 220 mg taken as one 110 mg capsule twice daily; 75 – 80 years consider 220 mg taken as one 110 mg capsule twice daily.

Patients with an increased risk of bleeding should be closely monitored clinically looking for signs of bleeding or anaemia. Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient. A coagulation test may help identify increased risk patients. Patients with gastritis, esophagitis, or gastroesophageal reflux consider 220 mg taken as one 110 mg capsule twice daily due to the elevated risk of major gastrointestinal bleeding. Patients with renal impairment and a high risk of bleeding consider 220 mg taken as one 110 mg capsule twice daily. Close clinical surveillance is recommended in patients with renal impairment.

Pradaxa is contraindicated in severe renal impairment (CrCL < 30 ml/ min). Concomitant verapamil 220 mg taken as one 110 mg capsule twice daily; Pradaxa and verapamil should be taken at the same time. No dose adjustment required but close clinical surveillance in patients < 50 kg.

Not recommended if liver enzymes > 2 Upper Limit of Normal (ULN). If switching from Pradaxa to parenteral anticoagulant wait 12 hours after the last dose of Pradaxa; if switching from parenteral anticoagulants to Pradaxa then Pradaxa should be given 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment; if switching from Pradaxa to VKA adjust the starting time of the VKA based on CrCL; if switching from VKA to Pradaxa stop VKA and give Pradaxa once INR <2.0. Cardioversion patients can stay on Pradaxa whilst being cardioverted. Not recommended aged < 18 years. Pradaxa should be swallowed whole with water, with or without food.

Patients should be instructed not to open the capsule as this may increase the risk of bleeding. Contraindications: Hypersensitivity to any component; severe renal impairment (CrCL < 30 ml/min); active clinically significant bleeding; organic lesion at risk of bleeding; impairment of haemostasis; hepatic impairment or liver disease expected to have any impact on survival; concomitant systemic ketoconazole, cyclosporine, itraconazole, tacrolimus. Warnings and Precautions: Not recommended if liver enzymes > 2 ULN. Haemorrhagic risk: Close clinical surveillance (signs of bleeding or anaemia) is recommended throughout the treatment period, especially when haemorrhagic risk is increased or risk factors combined. Factors which may increase haemorrhagic risk: age ≥ 75 years; moderate renal impairment (CrCL 30 – 50 ml/min); P-glycoprotein inhibitor co-medication; body weight < 50 kg; acetylsalicylic acid (aspirin); NSAID; clopidogrel; diseases/procedures associated with a risk of bleeding such as coagulation disorders, thrombocytopenia or functional platelet defects, active ulcerative GI disease, recent GI bleeding, recent biopsy or major trauma, recent ICH or brain, spinal or ophthalmic surgery, bacterial endocarditis. The measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.

Patients who develop acute renal failure must discontinue Pradaxa. If severe bleeding occurs, discontinue treatment and investigate the source of the bleeding. Avoid or use with caution agents which may increase the risk of haemorrhage. Avoid concomitant administration with P-gp inducers. Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate; prescribers should consult the Summary of Product Characteristics for further information. Procedures such as spinal anaesthesia may require complete haemostatic function. The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate; these patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma. Treat with caution patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events. Myocardial infarction. Contains Sunset Yellow (E110) which may cause allergic reactions. Interactions: Anticoagulants and antiplatelet aggregation agents; Strong P-gp inhibitors e.g. amiodarone, quinidine, verapamil, clarithromycin co-administration (close clinical surveillance); verapamil co-administration - reduce Pradaxa dose to 220 mg (see above); not recommended for concomitant treatment posaconazole, dronedarone, protease inhibitors including ritonavir and its combinations with other protease inhibitors; avoid with P-gp inducers e.g. rifampicin, St John’s wort, carbamazepine, phenytoin. Dabigatran etexilate and dabigatran are not metabolised by cytochrome CYP450 system, therefore related medicinal product interactions not expected. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa. Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran. Fertility, pregnancy and lactation: Avoid pregnancy during treatment. Do not use in pregnancy unless clearly necessary. Discontinue breast-feeding during treatment.

Undesirable effects: Most commonly reported adverse reactions are bleedings occurring in total in approximately 16.5 % in patients with atrial fibrillation treated for the prevention of stroke and SEE. Common (≥ 1/100, <1/10): anaemia; epistaxis; gastrointestinal haemorrhage; abdominal pain; diarrhoea; dyspepsia; nausea; genitourological haemorrhage (150 mg). Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes and NHS price: 110 mg 60 capsules £75.60 150 mg 60 capsules £75.60 Legal category POM MA numbers: 110 mg EU/1/08/442/007 (60 capsules) 150 mg EU/1/08/442/011 (60 capsules) 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 August 2011.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone). † ARR = Absolute risk reduction References: 1. Boehringer Ingelheim. Pradaxa® 150mg SPC. August 2011.

2. Boehringer Ingelheim. Pradaxa® 110mg SPC. August 2011. 3. BMJ Risk Calculation. http://clinicalevidence.bmj.com/ceweb/resources/calculate_ risk.jsp. Accessed April 2011. 4. Connolly S, Ezekowitz M, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-1151. 5. Connolly S, Ezekowitz M, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875-1876.

Date of preparation: August 2011 Job code: DBG 2983cs

For more information, including an educational pack, go to www.pradaxa.co.uk/SPAFeducationalpack or call the Pradaxa® information line on 0845 601 7880

Researchers examine role of intense glucose control, outer blood retina barrier in diabetic eye disorders

I

NTENSIVE GLYCAEMIC control in patients with Type 2 diabetes lowers the risk for developing eye problems, including retinopathy, in patients with higher cholesterol, lower plasminogen activator inhibitor and lower albumin-creatinine ratios, according to a new analysis of data from the Veteran Affairs Diabetes Trial (VADT).

New insight into effects on eye problems in diabetic patients could have an important impact on treatment. Diabetic retinopathy is the number one cause of blindness and 21% of

Any instance of retinopathy, progression of retinopathy, incidence of clinically significant macular oedema, or panretinal or focal/grid photocoagulation and viterectomy was considered one “composite eye outcome.”

patients with Type 2 diabetes have retinopathy when they’re diagnosed with diabetes, VADT researchers said. Plus, the incidence of retinopathy rises to 60% in the decade following that diagnosis, they said.

In the VADT trial, 1,791 patients were enrolled to see whether intensive control of glycaemia levels cut down on cardiovascular events compared to those under standard control.

In the study, eye complications were assessed using a photography procedure done by those not aware of the glycaemic control category of the patients. Complete data on these complications were available for 841 patients.

Any instance of retinopathy, progression of

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retinopathy, incidence of clinically significant macular oedema, or panretinal or focal/grid photocoagulation and viterectomy was considered one “composite eye outcome.”

Researchers found that higher HbA1c at baseline increased the risk for composite eye outcomes.

They also found that intensive glucose control was associated with significantly less worsening of ocular outcomes in patients with total cholesterol of at least 185mg/dl.

The same was found for those with albumincreatinine ratios below 7mg/g and for those with PAI1 below 17ng/dl.

Researcher Nasrin Azad, MD, of Edward Hines, Jr. VA Hospital, noted that the patients in the study were generally well-controlled in terms of cholesterol and blood pressure, suggesting that high levels of those parameters could not account for the eye outcomes.

“All patients, over the five years, had very good cholesterol and blood pressure,” she said.

In another study, researchers looked at the role of the outer blood-retina barrier of the eye in the development of macular oedema, finding that leaks in the barrier seem to be an important contributor to the condition and that interfering with the effect of vascular endothelial growth factor (VEGF) can help limit the leaks.

Breakdown of blood-retina barriers is a common pathological change and a major cause of vision loss in diabetic retinopathy.

But breakdown of the outer barrier - which separates the neural retina from the choroidal vasculature that’s responsible for 80% of the eye’s blood supply - has been studied less intensely than the inner barrier, which is assumed to be responsible for the pathological changes leading to vision loss.

Studying diabetic mice, researchers at the University of Oklahoma Health Sciences Center, along with Central South University in China, developed a new assay to see and quantify the leakage through the outer barrier -

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Toxins all around us might be taking aim at our metabolic systems

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ORE ATTENTION must be paid to the way “environmental toxins” - from pesticides to plastics - might be wreaking havoc on the body’s endocrine system, an expert said at the ADA Scientific Sessions.

“Can exposure to environmental toxins cause obesity?” asked Robert Lustig, MD, of the Division of Endocrinology at the University of California San Francisco.

Evidence is growing that it may indeed be the case, he said. They include oestrogens like the bisphenol-A found in plastic water bottles, phthalates used in plastic production, organochlorines that include many fertilizers like atrazine, the thiocynates in cigarette smoke and organotins found in fungicides and wood preservers.

Studies have shown that bisphenol-A correlates with cardiovascular disease and Type 2 diabetes 1 and that phthlalate urine metabolite levels are linked with higher waist circumference and insulin resistance.2 Researchers have also found that a persistent organic pollutant serum level has a dose-response relationship with the prevalence of diabetes.3 Many of the findings have only suggested a correlation and, for now, nothing more, Dr. Lustig said.

“It could be that this is just effect rather than cause,” he said. “And I’m the first to admit that. But it’s very worrisome because, number

a development they say will be helpful in future assessment of the diabetic eye.

Researchers also found that rodents with VEGF or VEGF’s receptor knocked out showed fewer breakdowns of the outer barrier.

Inhibiting extracellular-signal-regulated kinase (ERK) - a proteint that is a target of VEGF - reduced the number of outer-barrier leaks.

“Our study,” Oklahoma Health Sciences researcher Yun-Zheng Le, PhD, said, “may have significant implications to the mechanism and diagnosis of diabetic retinopathy.”

one, these pollutants are ubiquitous, they’re everywhere. They’re persistent in the environment. They don’t go away…. They may work antenatally to alter foetal programming, which may account for some of the things

“We have to do something to try to protect children, especially during the antenatal period.”

Dr. Robert Lustig

we’re seeing in toddlers. And ancestral exposure through epigenetics may alter subsequent generations.”

The U.S.’s National Institute of Environmental Health Sciences has a list of about 60 endocrine-disrupting chemicals, he noted.

“Does that mean we have to get rid of them?” Dr. Lustig said. “No, but we have to do something to monitor them, and we have to do something to try to protect children, especially during the antenatal period.”

Dr. Lustig’s chief concern, though, is fructose.

In the U.S., even as fat consumption has gone down, calorie intake has gone up - largely due

to an increase in carbohydrate consumption, predominantly from soft drinks, which are laden with fructose.

“The point is that chronic fructose exposure alone - alone, no other phenomenon - can cause a metabolic syndrome,” he said. “And that’s what the data show correlatively and we’re assessing this mechanistically right now.”

In another presentation addressing the risks particular to children, Alison Field, ScD, Associate Professor of Pediatrics at Children’s Hospital Boston, said the effects of obesity in children can have long-lasting and devastating effects.

Being overweight in childhood and adolescence has links to diabetes, asthma and ovarian cancer. And the evidence shows that overweight children tend to remain so.

“Childhood and adolescent obesity is associated with adverse health outcomes both during adolescence, early adulthood as well as much later in life,” she said. “Moreover, behaviours that are established early may influence their health for decades, not only the individual’s health but also the health of their offspring,” with problems often handed down “generation to generation.”

References: 1. Lang I, Galloway T, Scarlett A et al. JAMA 2008; 300(11): 1303-1310 2. Stahlhut R, Van Wijngaarden E, Dye T et al.

Environmen Health Perspect 2007; 115(6): 876-82 3. Lee D, Lee I, Jin SH, Steffes M et al. Diabetes Care 2007 Mar; 30(3): 622-28

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

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American Society of Clinical Oncology Reports from ASCO, Chicago by Dr. Sunil Upadhyay

Progress in lung cancer clinical research

L

UNG CANCER is the leading cause of cancer related deaths in the world.

The overall 5-year survival rate remains extremely low at approximately 15% despite recent progress. There are several reasons for this poor outcome. There is still a high prevalence of smoking related lung cancer all over the world. Unfortunately, despite increased levels of awareness, even at best centres, the early stage surgically resectable

Screening remains a hotly debated topic and despite poor success rates, it remains the best hope for early diagnosis of resectable disease.

tumours are less than 25%. Moreover, the cure rates even following surgery with or without adjuvant therapy with current agents remain low. For advanced disease at presentation, the long-term survival rates are also extremely low.

Despite low publicity, extensive research efforts are currently undergoing to overcome the burden of lung cancer. Screening remains a hotly debated topic and despite poor success rates, it remains the best hope for early diagnosis of resectable disease. Many prospective, uncontrolled trials using chest radiograph or CT scan based screening have looked at its merits and de-merits. These trials appear to have shown increased rates of early stage cancer detection and improved 5-year survival.1,2 However, there has been no improvement in the detection of advanced stage disease and mortality related to lung cancer. Moreover, there is a high rate of false–positive diagnosis, unnecessary treatment and anxiety in the screened population.

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trials (ALPI, ANITA, BLT, IALT & JBR-10) consisting of 4584 patients showed most of the benefit was seen in stage II & III patients with a trend in IB patients with platinum based adjuvant chemotherapy.

In 2010 the NSCLC meta-analysis collaborative group published another metaanalysis with two meta-analysis subgroups in it.4 The first one looked at surgery plus adjuvant chemotherapy vs surgery alone. The summary outcome was: 26 Trials: 18 platinum based with 8447 patients RFS: HR 0.83 (0.77-0.90), p<0.0001 OS: HR 0.86 (0.81-0.92), p<0.0001 5-year survival: 64% vs 60% ie 4% absolute benefit In this analysis, the benefit seen was only in stage IB, II and III cases but adjuvant chemotherapy had a negative effect in stage IA disease (HR 1.19). The second part of the metaanalysis, consisting of 12 trials (11 platinum based) with 2660 patients looked at surgery + radiotherapy + adjuvant chemotherapy versus surgery + radiotherapy only. The HR for RFS was 0.85 (0.77-0.93; p=0.0006) and OS 0.88 (0.81-0.97; p=0.009). Again, a significant gain was observed with adjuvant chemotherapy

The results of the National Lung Screening Trial (NLST) for selected high-risk populations (n=53,456) with 26,733 randomly assigned to chest radiograph and 26,723 to CT scan was published.3 The basic characteristics were representative of the general population of smokers in the USA. Subsequently, it was reported that although 24.2% of individuals were found to have suspicious lesions, only 3.6% were confirmed to be malignant.

However, there was a significant improvement in the lung cancer mortality (20.3%) as well as overall mortality (6.9%) in the CT scan group.

The long-term mature data from this and other studies is still awaited. Clearly CT scan based screening is not cost effective and banning tobacco which can reduce the mortality by 8090% by 2050 should remain the primary objective, a much more beneficial manoeuvre.

Adjuvant therapy in lung cancer: Unfortunately, even after surgical resection, the cure rate of lung cancer remains low, compared to breast and bowel cancers. There has been a number of adjuvant chemotherapy trials published over the last decade showing variable amounts of benefit.

Modern adjuvant therapy Study

Total no.

Stage

5 year survival Chemotherapy

Observe

p-value

ALPI

1088

I,II,IIIA

+1%

-

0.59

IALT

1867

I, II, III

44%

40%

0.03

BLT

381

I, II, III

58% (2 yr)

60% (2yr)

0.90

JBR.10

482

IB, II

69%

54%

0.002

CALGB

344

IB

60%

58%

0.125

ANITA

840

IB, II, IIIA

51%

43%

0.013 ASCO 2011

The three trials highlighted in yellow demonstrated significant benefits from platinum based adjuvant chemotherapy between 4-15%. Similarly, LACE meta-analysis including five of these trials using platinum based doublets demonstrated 5.4% 5-year survival benefits. The Lace meta-analysis of 5

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with an absolute gain of approximately 4%.

This is significant because it is potential cure and results in few extra lives saved. Despite these data, there remain many unresolved questions on the role of adjuvant chemotherapy. The number of patients with stage IA disease in these trials is small and most of the benefit for

New paradigm in the management of CRPC

T

HE RATE OF diagnosis of prostate cancer at an early stage of the disease is improving due to better awareness both amongst primary care physicians and the public at large. Use of radical surgery or radical radiotherapy with or without systemic therapies in a neo-adjuvant/adjuvant setting have definitely contributed to the higher proportion of cure and long-term survival rates over the last decade. However, many patients do relapse or present at an advanced stage of the disease. The mechanism is known to be an androgen receptor dependent pathology and blocking of the androgen receptor signalling is a natural manoeuvre for its control. Hormonal manipulation is the commonest first-line systemic therapy recommended in the majority of the guidelines along with loco-regional and supportive therapies. Unfortunately, sooner or later almost all develop relapse following initial response to gonadal androgen deprivation due to the development of resistance to surgical or medical castration. The exact mechanisms of the development of castration-resistant prostate cancer (CRPC) remains broadly unknown; though host factors, disease burden and tumour biology play an important role.

There have been limited treatment options for CRPC, which includes mitoxantrone, docetaxel

and bisphosphonates. With ongoing improvements in the understanding of the underlying pathology, a number of new management options are emerging.

A variety of novel systemic therapies are currently in clinical development with a diverse array of targets including persistent androgen

stage IB is possibly for tumours ≥4cm. The median age of the patients treated with adjuvant chemotherapy was 59-61 years and only 10% of the patients were ≥70 years or older. Moreover, most of the evidence is for cisplatin based doublets and only one trial was with a carboplatin based regimen.

These data suggest that adjuvant chemotherapy should be given in completely resected stage II & III and considered for high risk stage IB (≥4cm) tumours in patients with PS 0,1 who had uncomplicated surgical recovery within 6-8 weeks and are under 70 years of age. The chemotherapy should consist of platinum doublets, for purists cisplatin plus novelbine combination.

Clearly, we seem to have reached a plateau in terms of the efficacy of cytotoxic agents, particularly platinum doublets. It is also known that tumour growth is dependent on angiogenesis and multiple other growth factors, which suggests that targeting these mechanisms could have a variety of benefits.

Molecular agents targeting various pathways like TKI (gefitinib and erlotinib), angiogenesis (bevacizumab) and monoclonal antibody (cetuximab) have already reserved their place in the management of lung cancers. However, many other agents like imatinib, vandetanib, BIBW2992, BIBF1120, aflibercept and many others are being investigated. One of the advantages of these drugs is that they are oral

The incidence of neutropaenia including febrile neutropaenia, diarrhoea and death within 30 days of the last treatment was more common with the cabazitaxel.2

receptor activation, cell survival, angiogenesis, cell signalling, bone environment and the immune system. Some of these heterogeneous agents have already been tested in Phase III trials showing improved PFS, OS and QOL. The availability of these agents will radically change

the management of CRPC in our clinics.

Cabazitaxel is a microtubule-targeted agent, similar to docetaxel. Docetaxel together with prednisolone is the current standard firstline treatment option for CRPC.1 A randomised Phase III trial of cabazitaxel 25mg/m² compared with mitoxantrone 12mg/m² every 3 weeks along with prednisolone 10mg daily was reported to show a median survival of 15.1 months with cabazitaxel plus prednisolone compared with 12.7 months with mitoxantrone plus prednisolone (HR=0.70; p<0.0001). The median PFS also favoured cabazitaxel (2.8 vs 1.4 months). However, the incidence of neutropaenia including febrile neutropaenia, diarrhoea and death within 30 days of the last treatment was more common with the cabazitaxel.2 Cabazitaxel with prednisolone was the first regimen showing OS benefit in CRPC patients following progression with docetaxel hence it was approved by the FDA for suitable CRPC patients. Clearly, careful management of neutropaenia with G-CSF prophylaxis and diarrhoea is essential when using this regimen.

The other agent abiraterone acetate, a potent inhibitor of CYP17 and androgen synthesis was tested in a Phase III trial in patients CONTINUED ON PAGE 14 >

agents, have shorter half-lives and are less likely to give off-target effects. Actually, the management options for lung cancer are moving to the use of multi-targeted agents and identification of new targets for drug selection.

As we understand the influence of emerging targets, we also need to develop better biomarkers, preferably peripheral blood, understand their resistance mechanisms, better manage their toxicities and develop an optimal schedule of therapy.

References: 1. Bach PB et al; JAMA 297 (9): 953-961, 2007 2. Henschke C I et al; NEJM 355 (17): 1763 -1771, 2006 3. Aberle D R et al; J Natl Cancer Inst.; 102: 1771-1779, 2010 4. Lancet 375: 1267-1277, 2010

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American Society of Clinical Oncology Reports from ASCO, Chicago by Dr. Sunil Upadhyay

New paradigm in the management of CRPC < CONTINUED FROM PAGE 13

who had previously received docetaxel for CRCP. The primary end point was OS. The secondary end points were time to PSA progression, PFS and PSA response rate.

(25.8 vs 21.7 month). The 36 month survival probability was 31.7% in the sipulencel-T group compared to 23.0% in the placebo. The most frequent adverse effects observed with sipulencel-T were fever, chills and headache.

Androgen deprivation therapy is known to

Abiraterone 1000mg OD + Prednisolone 5mg BD N=797

mCRCP post-docetaxel n=1195

R 2:1 Placebo +Prednisolone 5mg BD N=398

After a median follow-up of 12.8 months, the OS was longer in the abiraterone group than in the placebo group (14.8 vs 10.9 months; HR=0.65; p<0.001) All secondary end points, including time to PSA progression (10.2 vs 6.6 months; p<0.001), progression free survival (5.6 vs 3.6 months; p<0.001) and PSA response rate (29% vs 6%; p<0.001) favoured the abiraterone group. Mineralocorticoid related adverse events, including fluid retention, hypertension and hypokalaemia were more frequent in the abiraterone acetateprednisolone group than in the placeboprednisolone group.3 Due to abiraterone acetate being a hormonal agent, this data resulted in a change of terminology from “hormone resistant” to “castration resistant” prostate cancer.

Last year the FDA approved sipulencel-T (Provenge), a novel autologous active cellular immunotherapy agent for the treatment of asymptomatic or minimally symptomatic metastatic CRPC, following publication of a double blind, multi-centre placebo controlled Phase III trial which provided evidence of its efficacy in reducing the risk of death.4 There was a relative reduction of 22% in the risk of death as compared with the placebo group (HR=0.78, p<0.03). This reduction represented a 4.1 month improvement in median survival

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be associated with bone loss and increased risk of fractures. Bisphosphonates are known to increase bone mineral density (BMD) and reduce the incidence of new fractures in men receiving androgen deprivation therapy for prostate cancer. Bone environment is a major factor in the development and progress of the disease related symptoms in patients with metastatic CRCP. Skeletal related events (SRE) such as bone pain, fracture and spinal cord compression are common. In metastatic CRCP, the poor bone health is mainly due to reduced bone mineral density, use of steroids and tumour induced biochemical changes in the bone. Use of zoledronic acid to improve the outcome and reduce SRE is well proven and hence universally recommended for suitable patients.5 Bone metastasis is associated with RANKL-mediated osteoclast activation leading to bone destruction and development of SREs. A new fully humanised monoclonal antibody denosumab binds to and inhibits the RANK ligand, an important activator of osteoclastic activity, which is known to be up regulated in CRPC. The results of a double blind, randomised, Phase III trial (n=1901) was presented at ASCO 2010 comparing denosumab 120mg subcutaneous to intravenous zoledronic acid 4mg every 4 weeks in metastatic CRPC.6 Denosumab significantly

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delayed the time to first SRE compared with zoledronic acid (HR=0.82, p<0.008). The median time to first SRE was 20.7 vs 17.1 months in favour of denosumab. It was concluded that denosumab was superior in delaying or preventing SREs in patients with metastatic CRCP. The Phase III trial data of ALSYMPCA is believed to show a statistically significant median overall survival benefit of 14.0 months with Alpharadin (radium-223 chloride) compared to 11.2 months with placebo (HR=0.699, p=0.0022). The ALpharadin in SYMptomatic Prostate CAncer patients is an international, randomised, double blind, multi dose, placebo-controlled study designed to evaluate the potential of alpharadin plus best standard care in management of symptomatic CRPC due to bone metastasis.

Skeletal related events (SRE) such as bone pain, fracture and spinal cord compression are common.

These new discoveries are producing promising results and brighter future for CRCP. They are resulting in improved OS, PFS and QOL, which is good news. The availability of these therapies with small median survival gains raises many questions like patient selection, cost and sequencing. One hopes that financial austerity measures will not deny suitable treatment options to patients in need of these new anti-cancer therapies.

References: 1. Tannock I F et al. NEJM 2004; 351: 1502-1512 2. de Bono J S et al. Lancet 2010; 376: 1147-1154 3. de Bono J S et al. NEJM 2011; 364: 1995-2005 4. Kantoff P W et al. NEJM 2010; 363: 411-422 5. Saad F et al. J Natl Cancer Inst 2002; 94: 1458-1468 6. Fazazi M A et al. JCO 2010; Vol.28. No.18S (June 20 suppl.) LBA 4507

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

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

candesartan cilexetil For all the right reasons

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

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

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

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

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

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

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

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

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

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

Code: TA110579d Date of preparation: May 2011

www.heartzone.co.uk

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

ESC Congress 2011 highlights "

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HE ESC CONGRESS 2011 in Paris has been a record breaking event" said Professor Michael Böhm, chairman of the ESC Congress Programme Committee. "With a total attendance of 32, 946 participants, this is our largest congress ever. We are especially pleased to see that more and more delegates are coming from outside Europe. Large delegations came from Brazil, Japan, China and India this year," said Professor Böhm.

"The medical community was eagerly waiting to hear about the results of important trials such as ARISTOTLE, Dai-VESSEL and RUBY-1.”

Professor Michael Böhm

"The quality of the scientific content at the ESC Congress attracts more and more participants each year," explained Professor Böhm. "The medical community was eagerly waiting to hear about the results of important trials such as ARISTOTLE, Dai-VESSEL and RUBY1 which were announced in Paris."

ARISTOTLE was probably the highlight of this congress as apixaban was shown to be superior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug was also associated with less bleeding and lower mortality rates.

Further interesting studies were the PRODIGY trial, which showed that a six months dual antiplatelet therapy after stent implantation (drug eluting and bare metal, stable and unstable patients) was as effective as 24 months, and associated with statistically lower bleeding hazards. The EXAMINATION trial,

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which demonstrated equivalence for a drug eluting stent (everolimus eluting) vs. bare metal stents (cobalt chromium) with respect to hard clinical endpoints but lower stent thrombosis and revascularisation rates up to one year, was also a highlight of the ESC Congress.

Professor Michel Komajda, President of the European Society of Cardiology, highlighted the fact that 2011 was the year of the registry: "Registries allow us to see if doctors are following guidelines. The PURE registry, for example showed worrying results: patients with previous cardiovascular disease are not receiving adequate treatment. The registry which enrolled 154,000 adults in 17 countries, found that in low income countries, 80% of cardiac patients received no medication at all, while in high income countries 11. 2% did not receive adequate treatment. There is still progress to make in prevention and treatment all over the world."

The ESC has launched its own registries.

Three of them were presented at ESC Congress 2011: Heart Failure, Atrial Fibrillation Ablation and Pregnancy and Heart Disease.

"So far, we had little data on how women with pre-existing heart disease fared during pregnancy. Complications are frequent and may be life threatening. Our registry is the first of the kind and results were worrying as maternal and foetal deaths were higher in this patient set than expected. This registry shows the need for collaboration between gynaecologists and cardiologists in the followup of pregnancies in women with heart disease" said Professor Komajda.

New clinical guidelines were also released by the European Society of Cardiology on the management of cardiovascular disease in pregnancy: "Because of the increasing prevalence of heart disease in young women, these guidelines emphasising the need for screening and risk assessment of pregnant women are extremely important," said Professor Komajda. Other guidelines announced by the ESC include new recommendations on peripheral artery diseases and updated ESC

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guidelines on the management of non-ST elevation acute coronary syndromes.

The ESC announced that it will extend its EurObservational registry project. New registries will include heart failure, atrial fibrillation and chronic ischaemic heart disease. EuroAspire IV will be launched in 2012 to collect data on epidemiology and risk factors across Europe.

Outside of Hot Lines and Clinical Trial Updates, the media had its favourite studies too.

Presentations on the beneficial effects of chocolate on the heart and on the positive effect of laughter on blood vessels were widely reported. On the contrary, other studies confirmed that overtime, job strain and anger are all cardio-toxic. "Increasingly, psychological factors are recognised as playing a major role in

"Because of the increasing prevalence of heart disease in young women, these guidelines emphasising the need for screening and risk assessment of pregnant women are extremely important."

Professor Michael Böhm

triggering heart disease," said Professor Kurt Huber, chairperson of the ESC Press Committee.

A public event was held on 28 and 29 August in front of the Town Hall in Paris in order to pass on the European Society of Cardiology's key messages to the public: Eat well, don't smoke, stop stressing and get up and exercise!

Cardiologists were present to give advice.

Around 3,000 Parisians and tourists visited the different stands and participated in activities such as baby gym, "zumba-fitness" and workshops on healthy cooking.

Date of preparation: February 2011 DSC/11/0006/G

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

The prevention of lifestyle diseases has finally reached the top table of the United Nations The General Assembly began a two-day summit with heads of government on non-communicable diseases in September, the first health issue on the UN agenda since HIV/AIDS in 2001

T

HE EUROPEAN SOCIETY of Cardiology, through the European Chronic Disease Alliance (ECDA), has urged European heads of state "to show leadership" and long-term commitment to the prevention of chronic non-communicable diseases at a "high level meeting" of the UN General Assembly in New York.1 This will be the first time ever that the UN has sought "action-orientated" commitments from governments and international organisations on the prevention and control of lifestylerelated diseases, and only the second time following its declaration on HIV/AIDS in 2001 that a health issue has attracted such high governmental attention. Measures to prevent non-communicable diseases, says the UN, have the potential to save "millions of lives" and "untold suffering".

The draft declaration on which the General Assembly began discussion was made public on 9th September. It aimed to make concrete commitments on access to effective medicines, the control of tobacco, the elimination of industrially produced trans-fats in foods, and the implementation of measures to reduce consumption of dietary salt, sugars and saturated fats and increase levels of physical activity in all populations.2 Agreement on all of these measures, says ESC spokesman Simon Capewell, Professor of Clinical Epidemiology at the University of Liverpool, UK, would be a major step forward in the prevention of cardiovascular and other non-communicable diseases. "Indeed," he notes, "the fact that they are even being discussed by the UN and endorsed by heads of state will give the whole question of prevention the importance it deserves. So far, although there has been great progress in some countries and in some areas of prevention, the global burden imposed by noncommunicable diseases is still overwhelming.

This is unacceptable and totally unnecessary."

Even within Europe, where anti-smoking and

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heart-healthy lifestyle campaigns have been introduced with some degree of success, the present facts underline the challenge: • Non-communicable diseases, such as heart disease, stroke, diabetes, common cancers and chronic diseases of the liver, kidney and respiratory system together cause 86% of all deaths in Europe • Up to 40% of European adults suffer some long-standing health problem related to chronic non-communicable diseases • Up to 80% of all healthcare expenditure in Europe is allocated to chronic diseases; cardiovascular diseases alone are estimated to cost the EU economy over 192 billion euros every year.3 Moreover, only 3% of all current healthcare spending is directed at prevention. The rest is consumed by treatment. While all these noncommunicable diseases are "treatable", rarely are they curable - although the majority of them are indisputably preventable. "Prevention," says Capewell, "is much more effective and more cost efficient than treatment."

Indeed, as recent research performed by Capewell and colleagues indicates, legislation or other measures to reduce salt or trans-fat consumption by just a small percentage would yield substantial personal health benefits and reductions in healthcare costs.4 Thus, the ESC welcomes the acknowledgement of trans-fats in the draft UN declaration and the specific recognition that "price and tax measures are an effective and important means of reducing tobacco consumption". In the past anti-tobacco campaigners have found tobacco interests lobbying ferociously against any fiscal measures on tobacco. This has frustrated national policies designed to protect citizens.

The ESC and associate organisations therefore welcomes the draft declaration's: • Agreement for countries to establish their own chronic disease policies by 2013

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• Recognition of non-communicable diseases (and their prevention) in all development and planning agendas • Commitment to accelerate implementation of the WHO Framework Convention on Tobacco Control (FCTC), which details price and tax (and non-price) measures to reduce the demand for tobacco.

There is also provision in the declaration for a follow-up meeting in 2014 to assess the impact of the measures agreed in New York. However, the ESC along with other organisations is disappointed that no targets have been set for this assessment. For example, says Capewell, the deletion of a 5mg target on salt intake per person per day which was in earlier drafts has now been removed. In its place are the promotion and initiation of "appropriate" costeffective interventions to reduce salt, sugar and saturated fat. "There are many references to 'as appropriate' placed against health measures," he says. "This lets governments off the hook."

The ESC and ECDA were also hoping that the draft would set an overall target for global mortality attributed to non-communicable disease based on the WHO recommendation to cut preventable deaths by 25% by 2025. But no defining target has been included in the present draft, so the impact will not be easily measured - and the impetus for countries to try harder less pronounced.

However, despite the disappointing nature of some items of the draft, the ESC welcomes the strong overall message of the Declaration and the new focus on chronic diseases at the highest governmental level. "Two years ago," says Capewell, "such a focus would have been unthinkable. Now, the whole summit process has moved preventable diseases right up to the top table. There is now a clear recognition of the scale of the problem and of the need to take action."

References are available on request.

European Medicines Agency

highlights

by Gary Finnegan

First ‘paediatric-use’ medicine approved

T

HE EUROPEAN Medicines Agency (EMA) has given the go-ahead for the first ‘children-only’ medicine.

Buccolam, a product for treating prolonged, acute, convulsive seizures in patients aged from three months to 18 years, is the first product to be granted a paediatric-use marketing authorisation (PUMA).

PUMAs are a new way for companies to bring drugs to the EU market, and marks a significant change for children’s medicines.

This new kind of license can be granted for medicines which are already authorised, but no longer patented, and which will be developed specifically for children. These medicines benefit from 10 years of market protection as an incentive.

A prerequisite for a PUMA is a paediatric investigation plan (PIP) which sets out the development of the medicine in children and has to be approved by the Agency’s Paediatric Committee (PDCO).

Dr. Agnès Saint-Raymond, Head of Human Medicines Special Areas at the EMA said that the medicines industry had given too little attention to the incentives offered by PUMAs and she hoped more companies would learn from this example.

To date, 26 applications for PIPs for PUMAs have been received by the Agency and seven opinions have been given by the PDCO. In the past, many medicines authorised in Europe were not studied adequately or authorised in children. This caused difficulties for prescribers and pharmacists treating children, as well as for patients and their parents.

Healthcare professionals typically worked out paediatric doses based on weight, but experts have long criticised this practice as it treats children as though they are simply “small adults”.

Richard Bergström Director General of EFPIA, the European pharmaceutical lobby group, welcomed the news but said the industry would “watch carefully what will happen in practice”.

He said medicines prescribed to children are

currently prepared by compounding in pharmacies and it is not clear whether this practice will now stop if PUMAs are to become commonplace.

“As an illustrative example, in the case of this first PUMA, the state-owned compounding company in Sweden (APL) already sells a competitor to Buccolam. Presumably, that product should now be taken off the market.

And that is only one example. A company with a PUMA will have to work hard to remove unfair competition in all 27 markets,” Bergström said.

So while industry analysts welcomed the dawn of a new era for children’s medicines, the full impact of the PUMA system is not year clear.

EMA is moving house The European Medicines Agency has signed a 25-year lease for office space in a new building in Canary Wharf in London. Europe’s drug regulator will move in 2014 when its leases expire on its current premises.

Its new home is still under construction and will be located at 25 Churchill Place. The Agency will lease the basement, promenade, ground and first nine office floors of the 20storey tower – making it the major tenant in the landmark building.

The deal follows a decision by the European Parliament’s budget committee - which holds the purse strings - giving the green light for the relocation plan.

The EMA said its new building will allow it to improve the efficiency of its use of space, reducing the overall floor-space rented and its annual expenditure. In a statement, the Agency hopes to cover the costs of relocation with the savings that these reductions will bring over the first ten years of its tenancy.

The company behind the development, the Canary Wharf Group, had consulted the EMA on the design of the building and will fit out the offices to the Agency’s specifications.

EU officials also noted that the new building will be environmentally friendly. It includes

photovoltaic cells and a “green roof” to enhance biodiversity and energy efficiency.

New medicines approved The EMA’s Committee for Medicinal Products for Human Use (CHMP) has published positive reviews for several new medicines. These include: Dexdor (dexmedetomidine), from Orion Corporation, intended for sedation of adult intensive care unit (ICU) patients.

Mercaptopurine Nova Laboratories (mercaptopurine monohydrate), an orphan medicine from Nova Laboratories Ltd, intended for the treatment of acute lymphoblastic leukaemia in adults, adolescents and children.

Plenadren (hydrocortisone), an orphan medicine from DuoCort Pharma AB, intended for the treatment of adrenal insufficiency in adults.

Vyndaqel (tafamidis), from Pfizer Specialty UK Ltd, an orphan medicine intended for the treatment of transthyretin amyloidosis in adult patients with symptomatic polyneuropathy, a severe, progressive orphan disease.

Zytiga (abiraterone acetate), from JanssenCilag International N.V., intended in combination with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

Incivo (telaprevir), from Janssen-Cilag International N.V., intended for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease. Telaprevir belongs to a new class of medicines for the treatment of chronic hepatitis that can directly inhibit viral replication in infected host cells which can lead to the eradication of the virus, and thus effectively to a cure of chronic hepatitis C.

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Journal reviews

by Bruce Sylvester

Reporting from some of the latest articles in

www.nejm.org

Longer initial paramedic CPR shows no added benefit

R

ESEARCHERS REPORT that extending initial cardiopulmonary resuscitation (CPR) by paramedics and firefighters from one to three minutes provides no additional survival benefit.

The study was led by Ian Stiell, MD, of the Ottawa Hospital Research Institute (OHRI), the University of Ottawa and the Resuscitation Outcomes Consortium. It is the largest randomised cardiac arrest trial ever, and it was published in the New England Journal of Medicine recently. A study involved nearly 10,000 cardiac arrest patients from North America.

Recent studies suggested that a longer period of initial CPR (up to three minutes) before analysing heart rhythm might improve survival.

Normally, paramedics and firefighters analyse heart rhythm immediately and provide brief CPR while preparing a defibrillator. But recent studies suggested that a longer period of initial

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CPR (up to three minutes) before analysing heart rhythm might improve survival.

In the new study, paramedics and firefighters across Canada and the U.S. were randomised into groups and instructed to provide 30 to 60 seconds of initial CPR or three minutes of initial CPR. During the study, the groups were switched.

Stiell and his colleagues reported that primary analysis of data from 9,933 patients showed no difference between the groups, with 5.9% of patients in both groups surviving to hospital discharge with satisfactory health.

But, notably, when the researchers analysed the actual length of CPR more closely, they found that survival tended to decrease as the length of initial paramedic CPR increased in patients who also received bystander CPR and had a heart rhythm amenable to defibrillation.

This subgroup represents approximately 10% of all patients in the study. There were no differences in other subgroups.

"Our study definitively shows that there is no advantage to a longer period of initial CPR," said Dr. Ian Stiell. "The data also suggest that patients who received bystander CPR may fare better with the shorter period of paramedic CPR. While there is some debate about the significance of this result, I think it is better to be on the safe side and stick with the traditional shorter initial CPR approach."

www.jama.ama-assn.org

Procedure used to increase circulation before and after angioplasty or stent placement appears to provide no benefit

A

MONG PATIENTS suffering a STEMI (ST-segment elevation) myocardial infarction, use of intra-aortic balloon counter-pulsation to increase blood flow before and after percutaneous coronary intervention does not result in a reduction in the amount of heart muscle permanently damaged, according to a study published recently in JAMA. The study was published early online to coincide with its presentation at the European Society of Cardiology Congress.

Manesh R. Patel, M.D., of the Duke Clinical Research Institute, Duke University Medical Center, Durham, N.C., and colleagues conducted a trial to determine whether, when compared with primary PCI alone (standard of

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care), IABC inserted prior to primary PCI reduced infarct size in patients with acute anterior STEMI without cardiogenic shock.

The randomised controlled trial, the Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI), included 337 patients, and it was conducted at 30 sites in nine countries from June 2009 to February 2011.

The investigators randomised subjects to receive IABC prior to primary PCI (with IABC continued for at least 12 hours), or primary PCI only. The primary endpoint was infarct size, expressed as a percentage of left ventricular (LV) mass and measured by cardiac magnetic resonance imaging (MRI). Secondary outcomes included all-cause death at six months and vascular complications and major bleeding at 30 days.

Secondary cardiac MRI findings were consistent with the infarct size findings, including average microvascular obstruction of 6.8% for IABC plus PCI vs. 5.7% for PCI alone.

The researchers found that the average infarct size was not significantly different between patients in the IABC plus PCI group and the PCI alone group (42.1% vs. 37.5%, respectively).

In higher-risk patients with other certain cardiac characteristics (proximal left anterior descending Thrombolysis in Myocardial Infarction flow scores of 0 or 1), the findings were similar (46.7% vs. 42.3%, respectively).

Secondary cardiac MRI findings were consistent with the infarct size findings, including average microvascular obstruction of 6.8% for IABC plus PCI vs. 5.% for PCI alone.

The authors wrote, “At 30 days, there were no significant differences between the IABC plus PCI group and the PCI alone group for major vascular complications and major bleeding or transfusions…By six months, three patients (1.9%) in the IABC plus PCI group and nine patients (5.2%) in the PCI alone group had died.”

The time to the composite end point of death, recurrent heart attack, or new or

worsening heart failure at six months was not significantly different between the two groups.

The researchers concluded that, unlike patients with cardiogenic shock for whom guidelines recommend intra-aortic counterpulsation, patients with high-risk anterior STEMI without shock do not achieve reduction in infarct size from early routine use of IABC. “Clinicians should continue to be vigilant about identifying patients who are at risk for rapid deterioration and who may benefit from counterpulsation (as seen with the crossover in this trial). Future studies should be aimed at identifying the patient features associated with early deterioration.”

“These findings support a standby strategy (rather than routine use) of IABC during primary PCI in high-risk anterior STEMI patients,” they added.

from 628 rural and urban communities across five continents, with 5,650 subjects reporting a prior coronary heart disease event and 2,292 subjects reporting a prior stroke.

The researchers found that the use of preventive drugs was low. Antiplatelet drugs (mainly aspirin) were taken by only a quarter of subjects with cardiovascular disease, ß-blockers by 17.4%, ACE inhibitors or ARBs by 19.5% and statins by just 14.6%.

www.thelancet.com

Drug use was highest in high income countries, where about two thirds of patients were taking antiplatelet drugs and statins, and about half of patients ß-blockers and ACE inhibitors or ARBs) and lowest in low-income countries, where less than 10% of patients used the therapies.

The economic wealth of a country accounted for two thirds of the variation in drug use, with individual-related factors (such as age, sex, education, smoking, hypertension and diabetes) affecting the rest.

The authors noted, “Even the use of accessible and inexpensive treatments such as aspirin (the most commonly used antiplatelet drug) varied seven-fold between low-income and high-income countries but the use of statins varied 20-fold.”

“Even in well developed health-care systems many patients are not receiving the best secondary prevention treatment, despite a wealth of preventative guidelines, continuing medical education, and revalidation programmes”, said Anthony Heagerty, MMS, MD from The University of Manchester, Manchester, UK in an accompanying comment.

Dr. Heagerty added, “In developing countries, the problems are more daunting and complex. Even in areas where cholesterol might be lower than in Europe or North America, the use of statins could reduce stroke and coronary artery disease. Education of doctors and patients must be a priority for governments.

PURE study highlights underuse of effective, low-cost treatments for heart disease and stroke

I

NEXPENSIVE DRUG treatments for cardiovascular disease that save lives are underused worldwide, researchers reported at The European Society of Cardiology Congress in Paris, France, and published simultaneously online in The Lancet.

Investigators found that about 60% of individuals with heart disease and up to half of patients who have had a stroke are not taking any of the four effective drug types. Underuse is especially rampant in low-income countries, where about 80% of patients reported receiving no essential drugs.

The four drug types measured were antiplatelet drugs (mainly aspirin), ß blockers, angiotensin-converting-enzyme [ACE] inhibitors or angiotensin-receptor blockers [ARBs], and statins.

The PURE study evaluated the use of these four key secondary preventive and bloodpressure-lowering drugs in three high-income, ten middle-income, and four low-income countries. (High income: Canada, Sweden, United Arab Emirates. Middle-income: Argentina, Brazil, Chile, Malaysia, Poland, South Africa, Turkey, China, Colombia and Iran. Low-income: Bangladesh, India, Pakistan and Zimbabwe).

The investigators enrolled 153, 996 adults

The economic wealth of a country accounted for two thirds of the variation in drug use, with individual-related factors affecting the rest.

Partnership with industry, as employed in the fight against HIV, could reap immediate and valuable rewards where cheap generic drugs are not available.”

BMJ www.bmj.org

Large variation found in bowel reoperation rates in UK

R

ESEARCHERS REPORT a large variation in unplanned reoperation rates after colorectal surgery in English NHS hospitals, according to a study published recently in the British Medical Journal.

The investgators suggest that reoperation rates could be used alongside other quality measures in order to improve surgical performance nationwide.

Imperial College London researchers used Hospital Episode Statistics (a dataset covering the entire English NHS) to evaluate national reoperation rates after colorectal surgery and to investigate the feasibility of using reoperation as a quality indicator.

They evaluated data on 246,469 patients in 175 English hospital trusts who underwent colorectal surgery for the first time between April 1, 2000 and March 31, 2008.

A total of 15,986 (6.5%) patients required reoperation.

Emergency patients experienced slightly higher reoperation rates than elective patients.

Male patients, and those with inflammatory bowel disease or other existing conditions, were also more likely to need further unplanned surgery.

The researchers found substantial variation in reoperation rates among hospital trusts and individual surgeons.

There was a fivefold difference in highest and lowest reoperation rates after elective surgery (14.9% v 2.8%) among trusts performing more than 500 procedures, and a threefold difference in reoperation rates in trusts performing more than 2,500 procedures during the study period (11.5% v 3.7%).

The authors asserted that their findings support the feasibility of using reoperation rate as a quality indicator derived from routinely collected data across a range of surgical specialties. And they suggest that "reoperation rates, along with existing quality indicators such as mortality, could offer a powerful means of checking quality of surgical care."

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Medical news from around the world

by Gary Finnegan

World Health Matters CANADA Canadians counting the cost of common cold MEDICAL RESEARCHERS HAVE highlighted the impact of colds and flu on school absenteeism, the workplace and the economy in an effort to convince policymakers to invest in preventative measures.

A team at the Department of Family Medicine at Queen's University in Ontario, Canada, reviewed more than 80 published clinical studies by over 300 researchers and issued a report entitled “Why the Common Cold and Flu Matter”.

As Canada settles into another deep winter, millions are expected to suffer flu-like symptoms, often leading to absenteeism due to illness or the need to take care of a sick relative.

As Canada settles into another deep winter, millions are expected to suffer flu-like symptoms, often leading to absenteeism due to illness or the need to take care of a sick relative.

One third of Canadian adults have a sore throat, cold or flu in any given month, according to the report, with symptoms found to be more common in women than men.

Women are also more likely to self-treat at the first signs of cold or flu and tend to consult a doctor more frequently than men.

Cough and cold remedies are the second most commonly used medications in Canada, with more than $300 million a year spent on over-thecounter cold and flu treatments and prescription antibiotics. These products, say the authors, for the most part, neither “ameliorate symptoms nor change the course of the illnesses”.

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However, researchers argue that prevention can play a role in reducing the spread of illnesses. School-aged children and young adults play a significant role in the spread of respiratory illnesses and studies show a spike in colds and flu within the first two weeks of students’ return to school in September.

While some companies complain of lost productivity due to absent staff, the report argues that adults also play a significant role in the spread of infection and may exacerbate a local outbreak by turning up to work when they are ill.

Drawing on a U.S. study, the authors say it costs employers twice as much in productivity losses for employees who come to work sick than for those who stay home.

All of this infection adds up to a significant economic cost as researchers cite direct costs due to lost productivity from colds at $25 billion in the U.S. Taking into consideration both indirect (lost productivity) and direct (doctor visits and medicine) costs of colds, the figure in the U.S. annually is $40 billion.

“Preventative measures that result in even a modest reduction in colds and flu would have a significant impact on reducing costs to the healthcare system and impact on the economy,” the researchers conclude.

GERMANY German regions performing ‘harmful’ hysterectomies HYSTERECTOMY RATES VARY markedly from one region to another in Germany but around 4% of all such operations are potentially harmful, according to a new national study.

The decision to operate can be influenced by a range of non-clinical factors, say the authors, including what kind of health insurance the patient has and the gender of the doctor.

With such variation in the rate and reason for hysterectomies, experts have grown concerned that some surgeons are performing unnecessary operations which carry significant risks for the patient.

The risk of stroke and heart disease in young

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women is elevated following hysterectomy combined with the removal of both ovaries, research has shown. This prompted Dr. Andreas Stang to investigate hysterectomy practice across Germany and examine the factors influencing the decision to perform the operation.

The overall rate of hysterectomy in Germany was 362 per 100,000 person-years. 55% of hysterectomies for benign diseases of the female genital tract were performed transvaginally. Bilateral ovariectomy was performed concomitantly in 23% of all hysterectomies, while 4% of all hysterectomies were subtotal.

The range of hysterectomy rates across the country was startling, according to the authors.

The rate for benign disease was lowest in Hamburg (213.8 per 100,000 women per year) and highest in Mecklenburg–West Pomerania (361.9 per 100,000 women per year).

Factors influencing the hysterectomy rate included not just the patient’s concomitant illnesses, but also her social status, her health insurance class and the sex of the gyneacologist.

While the researchers note that removal of the uterus is among the commonest procedures in surgical gynaecology, they found that 4% of women under 50 who underwent hysterectomy for an indication other than cancer had a bilateral oophorectomy in the same operation, even though recent studies have shown that this is associated with an increased risk of stroke and coronary heart disease.

Factors influencing the hysterectomy rate included not just the patient’s concomitant illnesses, but also her social status, her health insurance class and the sex of the gyneacologist.

The newly-published study is based on statistics from 2005 and 2006 when 305,015 hysterectomies were performed nationwide.

The authors said that at 3.6 per 1,000 personyears, Germany’s overall hysterectomy rate is higher than Sweden (2.1 per 1,000 personyears) but lower than the USA (4.9 per 1,000 person-years) and Australia (5.4 per 1,000 person-years).

Dr. Stang and colleagues said that there are alternatives to hysterectomy for treating several common benign diseases. For example, in cases of genital prolapse without uterine pathology, doctors should first explore the options for conservative treatment or uterus-sparing surgery before considering hysterectomy.

BRAZIL Innovative prevention programme in schools reduces parents’ heart risk A GROUND-BREAKING multidisciplinary education programme in cardiovascular prevention which targeted school children has had a remarkable knock-on effect – the initiative helped to reduce the cardiovascular risk of the children’s parents.

The Brazilian researchers behind the project say their experience suggests focusing cardiovascular prevention programmes on children first can lead whole families to adopt healthier lifestyles.

Dr. Luciana Fornari, from the University of Sao Paulo, Brazil, said she was inspired to develop the scheme after seeing how her own children managed to influence the family’s habits based on what they had learned in school.

The study, which has garnered considerable media attention in Brazil due to its social and political implications, is prompting a rethink of health promotion strategies by Brazilian officials.

200 children aged from six to 10 years from a private school in the city of Jundiai, 60km from Sao Paulo, and their 323 parents were divided into two groups as part of the study.

Children in the control group (which assessed 161 parents with a mean age of 39 years) were provided with written educational

material at the beginning and middle of 2010.

The material included information about benefits of healthy life style, such as a fat and sugar-free nutrition, more physical exercises and avoidance of tobacco.

Children in the intervention group (which assessed 162 parents with a mean age of 38 years) were issued with the same material and also exposed to a weekly educational programme about cardiovascular prevention that aimed to teach, in different ways adapted to their ages, concepts of healthy nutrition, tobacco avoidance and the importance of physical activity.

200 children aged from six to 10 years from a private school in the city of Jundiai, 60km from Sao Paulo, and their 323 parents were divided into two groups as part of the study.

The programme included educational films and plays, and discussion about healthy lifestyles with the multidisciplinary team.

In both groups, investigators collected data from parents and their children at the beginning and end of 2010, including nutritional and exercise surveys measures of weight, height, waist circumference, arterial blood pressure and laboratory exams.

When the investigators analysed the parents’ Framingham cardiovascular risk, they found that 9.3% of the control group (15 parents) and 6.8% (11 parents) of the intervention group had more than 10% year risk of cardiovascular heart disease (CHD) in the next 10 years.

After the children’s educational programme, the intervention group had a reduction of 91% in the intermediate/high Framingham CVD risk group (1 parent with >10% year risk of CHD) compared with 13% reduction in the control group (13 patients with >10% year risk of CHD), p=0.0002.

This, the researchers concluded, suggests cardiovascular prevention should begin in schools.

SPAIN Almost 17% of Spanish children suffer tics SPANISH NEUROLOGISTS have revealed new data showing that tics are more common than previously thought.

A new study led by Dr. Esther Cubo, researcher from the Yagüe de Burgos General Hospital, shows that 16.86% of children have tics. The incidence is greater in boys than girls, and they tend to disappear or reduce with age, according to the results which have been published in the journal Pediatric Neurology.

“Tics are a very common disorder,” Dr. Cubo said. “Before, it was believed to be a rare condition, and since studies were only conducted for people that consulted the doctor, only severe tics were observed. Now we have noticed that most are mild disorders that do not have any functional repercussion.”

Although various epidemiological studies have been conducted, this is the second in Spain, with a larger population size than the first one, which only recorded data in two school centres.

The new study is based on the prevalence of tics in a sample of 1,158 school children in the province of Burgos, but the authors believe that these figures can be extrapolated to the rest of the Spanish population.

The most severe diagnoses were chronic motor tic disorders (6.07%) and Tourette’s syndrome (5.26%).

“There is still a lack of knowledge, even among medical staff, as to why diagnosing tics has to be associated with coprolalia - insults, swear words,” highlights Cubo. “In fact, it is classified as being a rare disease, but we have to consider it as being common so that it is diagnosed correctly.”

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FDA highlights

by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs Triptorelin therapy reduces rate of chemotherapy-induced early menopause among women with breast cancer

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SE OF THE hormone analogue triptorelin to temporarily suppress ovarian function reduces the rate of chemotherapy-induced early menopause in women with breast cancer, researchers reported in the recent issue of JAMA. The authors noted that about 6% of women with breast cancer are diagnosed before age 40 years, and that most of these patients receive systemic chemotherapy, hormonal therapy, or both. Chemotherapy in these patients is associated with at least a 40% incidence of longterm amenorrhoea, they said. No standard strategies for preventing chemotherapy-induced ovarian failure have yet been developed.

However, preclinical data have suggested that temporary ovarian suppression with a gonadotropin-releasing hormone (GnRH) analogue during chemotherapy reduces ovarian toxicity.

Lucia Del Mastro, M.D., of the Istituto

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Nazionale per la Ricerca sul Cancro, Genova, Italy, and colleagues conducted a Phase 3 trial assessing temporary ovarian suppression by the GnRH analogue triptorelin for reducing the incidence of early menopause in young women with breast cancer undergoing supplemental or neoadjuvant chemotherapy.

The randomised trial was conducted at 16 sites in Italy. Investigators enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer, and all subjects were candidates for adjuvant or neoadjuvant chemotherapy.

Prior to initiating chemotherapy, the subjects were randomised to chemotherapy-only or chemotherapy in combination with triptorelin.

Triptorelin was administered intramuscularly at least one week prior to initiation of chemotherapy, and then every four weeks for the duration of chemotherapy.

The investigators reported that the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an

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absolute difference of 17%.

The number needed to treat (the number of patients that need to be treated with triptorelin to prevent early menopause in one patient) was six.

Only triptorelin treatment associated with a significant reduction of the risk of developing early menopause; age and the type of chemotherapy did not significantly affect the risk.

The researchers reported resumption of menses in 60 patients in the chemotherapyonly group (49.6%) and in 88 patients in the chemotherapy-plus-triptorelin group (63.3%).

"In conclusion, our results suggest that temporarily suppressing ovarian function by administering triptorelin reduces the incidence of chemotherapy-induced early menopause.

This treatment can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy," the authors said.

In an accompanying editorial, Hope S. Rugo, M.D., and Mitchell P. Rosen, M.D., of the University of California, San Francisco, wrote that the findings are an important addition to the study of ovarian preservation for women with cancer. "Given that patients with hormone receptor-positive disease in the current study who had evidence of ovarian recovery were immediately suppressed without data on long-term recovery and that breast cancer outcome data are not available, and given as well the potential adverse effects on disease outcome, the use of GnRH agonists concomitant with chemotherapy cannot be recommended as a standard treatment and should be approached with caution in women with hormone-sensitive disease."

The editorialists added, "International guidelines recommend discussion of fertility options before starting chemotherapy, and when possible before surgery, to allow optimal timing for consultation and oocyte [egg cell] harvesting. When feasible, and for patients

with hormone-insensitive disease, GnRH agonist therapy to suppress ovarian function during chemotherapy is an additional treatment that can potentially expand fertility possibilities. Although recovering menses is not the same as fertility preservation, it is one step in the right direction."

Antibiotic prophylaxis better than cranberry capsules for prevention of urinary tract infections

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MONG PREMENOPAUSAL women who have repeated urinary tract infections (UTIs), prophylactic use of the antibiotic trimethoprim-sulfamethoxazole (TMP-SMX) is more effective than cranberry capsules for preventing recurrent infections.

Researchers reported this finding in the recent issue of Archives of Internal Medicine.

TMP-SMX appeared to be more effective at preventing UTIs than cranberry capsules, but the researchers noted that achieving this result also seemed to increase the rate of antibiotic resistance.

Mariëlle A.J. Beerepoot, M.D., from the Academic Medical Center, Amsterdam, and colleagues conducted a double-blind noninferiority trial of cranberry capsules and TMPSMX. They enrolled 221 premenopausal adult women who had reported at least three symptomatic UTIs in the previous year.

The subjects were randomised to either TMP-SMX (480mg at night, plus one placebo capsule twice daily) or cranberry capsules (500mg twice daily, plus one placebo tablet at night) for 12 months.

The investigators evaluated the clinical status of each subject once a month (and for three months after stopping the study medication) using urine and feces samples and a questionnaire. Subjects also submitted urine dipslides when they experienced UTIlike symptoms.

At 12 months, the average number of clinical recurrences was 1.8 in the TMP-SMX group and 4.0 in the cranberry capsules group. Recurrence occurred, on average, after eight months in the drug group and after four months in the cranberry capsules group.

TMP-SMX appeared to be more effective at preventing UTIs than cranberry capsules, but the researchers noted that achieving this result also seemed to increase the rate of antibiotic resistance; antibiotic resistance rates tripled in the pathogens found in patients in the TMPSMX group. But three months after the drug was discontinued, resistance rates had returned to baseline levels.

"From clinical practice and during the recruitment phase of this study, we learned that many women are afraid of contracting drugresistant bacteria using long-term antibiotic prophylaxis and preferred either no or nonantibiotic prophylaxis," they report. "In those women, cranberry prophylaxis may be a useful alternative despite its lower effectiveness."

Propranolol treatment gets better outcomes for infantile vascular tumours

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OMPARED WITH oral corticosteroids, treatment of infantile haemangiomas (IHs) with the beta-blocker propranolol produced higher rates of lesion clearance, fewer adverse effects and fewer surgical interventions after treatment, researchers reported in a report published online recently by Archives of Dermatology.

As background the authors noted that IH usually grows rapidly in the first three to 12 months of life, and then regresses from age three to seven. But regression may not completely improve the patient's appearance.

When IH goes untreated, patients may experience ulceration, scarring, recurrent bleeding and impairment of vision, hearing, feeding and defecation. In complicated cases, patients may develop heart problems, structural abnormalities, cosmetic disfigurement or psychosocial problems.

"Therefore, IHs often require systemic, surgical and/or laser treatment to avoid these adverse effects," write the authors.

Corticosteroids are often used to treat the disorder, usually oral prednisolone. But, data from recent studies suggest that propranolol

might effectively treat IH. Cynthia J. Price, M.D., formerly of the Miller School of Medicine, University of Miami, and colleagues evaluated propranolol for patients with IH and with no cardiac abnormalities, also gathering information about optimal length of treatment, associated adverse effects and relapses when treatment ends.

Between February 2005 and October 2010, they conducted a multicentre, retrospective review of the medical charts of 110 patients with IHs. They used photographs and clinical results to divide patients into two groups: those whose IH was cleared by 75% or more (defined as a reduction of at least 75% in the tumour's volume) and those whose tumour clearance was less than 75%.

On average, treatment with propranolol lasted 7.9 months and treatment with oral corticosteroids lasted 5.2 months.

The researchers found that, out the 68 patients who received propranolol, 56 (82%) had tumour clearance of 75% or more, compared with 12 (29%) of 42 patients who received oral corticosteroids.

Adverse events were reported in three patients receiving propranolol and all 42 patients receiving corticosteroids.

Among the patients who received propranolol, relapse occurred after treatment ended, but the researchers noted improvements after another course of treatment. Eight patients (12%) in the propranolol group and 12 patients (29%) in the corticosteroid group needed further surgery.

"In conclusion, our study showed that propranolol therapy was more effective in lesion clearance, required fewer surgical referrals after treatment and demonstrated superior tolerance, with minimal adverse effects," the authors wrote. "Propranolol proved to be safe in treating IH in our patients as no major adverse effects occurred. Also, propranolol therapy was more cost-effective, with a cost reduction of more than 50% per patient."

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View from the waiting room

by Steve Devrell

Aspirin - the wonder drug

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WAS BROUGHT UP in the generation that had a very modest medicine cabinet. A tin of plasters, some out of date TCP, Calamine lotion and a good old fashioned bottle of aspirin. That was it, the full gambit of household remedies in the 1950s. My mother’s views on taking tablets was so sceptical that I had to be burning up or wracked with pain before she opened the aspirin bottle, removed the small dab of cotton wool and reluctantly gave

Today, it is still arguably the most widely used drug in the world with over 100 billion tablets or 40,000 tons of the drug being consumed every year.

me half a tablet. Little did I know at the time, that this humble half tablet was the most amazing drug in the whole world. Not my words, but the words of Professor Alistair Watson, consultant gastroenterologist at the University of East Anglia. He concedes that penicillin has probably saved more lives, but he maintains in terms of broad applications, nothing has come close to aspirin.

Part of the great benefits of aspirin is its modest price and it was the drug that kick started the pharmaceutical industry.

Today, it is still arguably the most widely used drug in the world with over 100 billion tablets or 40,000 tons of the drug being consumed every year. But aspirin is one of the oldest natural remedies in existence. The basis of aspirin is salicylic acid which is found in plant extracts including willow bark. The medicine men of the North American tribes used the bark of willow trees (usually in the form of tea) to treat pain and fever. Even earlier, Ancient Egyptians used salicylic acid from dried myrtle leaves to treat muscle pain.

Hippocrates, the father of modern medicine, who lived sometime between 460 BC and 377 BC prescribed willow

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bark tree, which was crushed into a powder, for the pain of childbirth.

An additional source of salicylic acid was found in 1835 by the German chemist Karl Jakob Lowig. It was found in Meadowsweet (spiraea ulmaria), a wild flowering plant that grows on the riverbanks over much of Europe. Twenty years later salicylic acid had been successfully synthesised in laboratories for the first time, paving the way for mass production. Most people who tried the new drug found it was extremely effective at both pain relief and reducing fever. But it did have certain unpleasant side effects. Salicylic acid often caused irritation to the mouth and throat as well as upset stomachs. Indeed for a minority who used salicylic acid, it caused more problems than it solved.

The solution was provided by a 29-year old pharmaceutical student working at the German pharmaceutical company Bayer. His name was Felix Hoffmann. There was a personal reason why Hoffmann got involved in the problem. His father suffered from arthritis, but could not tolerate salicylic acid. In 1897, Hoffmann claims to have invented acetyl salicylic acid (ASA) – a new formulation of salicylic acid, which did not have the same side effects of its predecessor. It is perhaps worth sounding a note of caution to Hoffmann’s claims. Although Bayer’s official version of events awards the discovery of this crucial modification of the drug to Hoffmann, there is a conflicting story. A Jewish chemist by the name of Arthur Eichengrun later claimed that he was the lead investigator in the discovery, but records of his contribution were expunged under the Nazi regime.

Whoever was responsible for the main research into this drug, didn’t really matter at the time because Bayer initially decided to shelve the project. Bayer was far more interested in Hoffmann’s other discovery, diacetylmorphine. Bayer wanted to use this drug, which was given the brand name Heroin, in its cough medicine!

By 1899, after further successful tests, the new drug acetyl salicylic acid was launched and given the brand name Aspirin derived from the old botanical name for meadowsweet.

Aspirin was an instant success and its popularity grew rapidly in the first half of the twentieth century, spurred on by its

supposed effectiveness in the wake of the Spanish flu pandemic of 1918. However, recent research suggests that the high death toll of the flu pandemic was partly due to aspirin itself. As the largely unsupervised doses lead in some cases to toxicity, fluid in the lungs and the development of secondary bacterial infections and eventual mortality.

Nevertheless, aspirin’s profitability led to fierce competition and the proliferation of aspirin brands and products, especially after the American patent held by Bayer expired in 1917. Furthermore, after Germany’s surrender in the First World War and as part of war reparations specified in the 1919 Treaty of Versailles, Aspirin (along with Heroin) lost its status as a registered trademark in France, Russia, the UK and the USA. Today Aspirin with a capital ‘A’ remains a trademark still owned by Bayer. The trademark Aspirin is still used in over 80 countries worldwide.

Bayer was far more interested in Hoffmann’s other discovery, diacetylmorphine... which was given the brand name Heroin, in its cough medicine!

In the mid 20th century, aspirin declined in popularity after the market releases of paracetamol in 1956 and ibuprofen in 1969, but then almost miraculously, the little white pill was found to have other potentially lifesaving properties. It has become, and I am one of its converts, a daily ritual for many.

On doctors’ advice, people over 50 are now regularly taking a tablet a day to help reduce the risks of heart attacks or strokes as it has been proven to improve the flow of blood to the heart and brain.

The humble aspirin has also been found to have many other benefits. Until I started my daily dose recently, I only used aspirin to help reduce the risk of DVT on long haul flights. It was my only concession to using this drug as I preferred the ‘sexier’ and more costly alternatives if ever I needed pain relief. But the aspirin has truly become a wonder drug for the many important benefits it can offer.

A 2010 study by Oxford University involving over 25,000 patients showed that taking a small 75mg daily dose of aspirin for between four and eight years substantially reduces death rates from a range of common cancers by at least a fifth and the reduction of risk continued for 20 years in both men and women. For specific cancers the reduction was about 40% for bowel cancer, 30% for lung cancer, 10% for prostate cancer and 60% for oesophageal cancer.

Other cancers were tested, but the results were difficult to quantify because there was not enough data. There have been other studies that claim low dose benefits from taking aspirin, including one in 2009 from Yale University that claimed aspirin might prevent liver damage. Aspirin has also been theorised to reduce cataract formations in diabetic patients. There has even been a claim in a 2010 article in the Journal of Clinical Oncology, that aspirin may reduce the risk of death from breast cancer.

These are all very strong and hopefully valid claims for this little 2p tablet. I am no medical man, but I do have a natural caution as there is obviously tremendous commercial value involved in these claims. There are also proven adverse effects attached to taking aspirin, not least of all gastrointestinal bleeding. There are some enteric coated formulations of aspirin that are advertised as being gentle on the stomach. Some companies have also introduced ‘buffering agents’, which are designed to prevent the aspirin from concentrating on the walls of the stomach. Taking aspirin with vitamin C is a more recently investigated method of protecting the stomach lining.

There is of course the problem of overdosing, which can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute overdose has a mortality rate of 2%.

Chronic overdose is more commonly lethal, with a mortality rate of 25%.

This aside, the benefits as outlined to me by my GP seems to far outweigh the risks, which must be the crucial criteria for all medicines. I have been persuaded to give up my 60 years without regular medicine to put my trust in this little white pill. I am sure I am doing the right thing!?

Steve Devrell is a retired deputy head teacher who contributes regularly for many local and national publications.

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LET’S THINK

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

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