Evidentia Feb/March 2011 by Peter Mas-Mollinedo

Volume 5 Issue 1 | February/March 2011 | ISSN 1753-464X

One in 100 deaths worldwide are ‘due to passive smoking’ Big advances seen in breast cancer survival Depressive symptoms can have important effect on womens’ CV health Immigrant children in USA ‘less likely to have asthma’

Conference reports from: Chicago, Stockholm and Washington

A real advance in the delivery of breakthrough cancer pain relief 1–6

Introducing PecFent®. Powered by the innovative PecSys® technology, PecFent helps optimise intranasal fentanyl delivery by transforming aqueous droplets into a gel matrix on the nasal mucosa. This allows rapid but controlled absorption of fentanyl, in minutes. PecFent with PecSys helps match treatment to the profile of breakthrough cancer pain.2–10 ADVERSE EVENT REPORTING Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Archimedes Pharma UK Ltd by e-mail to PVArchimedesPM@akos.co.uk or by telephone on +44 (0)1582 766 339. ABBREVIATED PRESCRIBING INFORMATION. Please refer to the full Summary of Product Characteristics (SPC) before prescribing. PecFent 100 micrograms and 400 micrograms/spray, nasal spray solution (fentanyl pectin nasal spray): Each ml of solution contains either 1,000 µg or 4,000 µg fentanyl (as citrate), delivered using the PecSys gelling system. Indication: Management of breakthrough pain (BTP) in adults who are already receiving maintenance opioid therapy for chronic cancer pain. Maintenance therapy is defined as at least 60mg of oral morphine daily, at least 25 µg of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer. Dosage and Administration: Treatment should be initiated by and remain under the supervision of a physician experienced in the management of opioid therapy in cancer patients. PecFent should be titrated to an effective dose that provides adequate analgesia and minimises adverse reactions. Initial Dose: One 100 µg spray, patients must wait at least 4 hours before treating another episode of BTP with PecFent. Titration: If the initial dose is unsuccessful, a higher dose of two 100 µg sprays (one in each nostril) can be used for the next BTP episode. If this dose is not successful, the patient may be prescribed a bottle of PecFent 400 µg/spray and instructed to change to one 400 µg spray for their next episode of pain. If this dose is not successful, the patient may be instructed to increase to two 400 µg sprays (one in each nostril). Once an effective dose is reached, it should be confirmed for two consecutively treated episodes of BTP. Maintenance: Patients should continue to take their established

NEW

effective dose up to a maximum of 4 doses per day. Dose readjustment: The dose of PecFent should only be increased if the current dose fails to adequately treat BTP for several consecutive episodes. Review the background opioid therapy if the patient consistently presents with more than 4 BTP episodes per 24 hours. If adverse reactions are intolerable or persistent reduce PecFent dose. Discontinuation of therapy: PecFent should be discontinued immediately if the patient no longer experiences BTP episodes. Treatment for background pain should be kept as prescribed. If all opioid therapy is to be discontinued, the patient must be closely followed by the doctor as gradual downward titration is necessary to avoid withdrawal effects. Contraindications: Hypersensitivity to the active substance or excipients. Use in opioid naïve patients. Severe respiratory depression or severe obstructive lung conditions. Interactions: Potential interactions may occur when PecFent is given concurrently with agents that affect CYP3 A4 activity. The use of other central nervous system depressants may produce additive depressant effects. PecFent is not recommended for use in patients who have received MAO inhibitors within the previous 14 days. Concomitant use of partial opioid agonists/antagonists is not recommended. Concomitant use of nasally administered vasoconstrictive decongestants during titration is not recommended. Concomitant use of other nasally administered products should be avoided within 15 minutes of dosing with PecFent. Precautions: PecFent contains fentanyl in an amount that can be fatal to a child, therefore it should be kept out of the reach and sight of children. Tolerance and dependence may develop upon repeated administration of opioids such as fentanyl. Fentanyl use has a clinically significant risk of respiratory depression, however chronic opioid use lowers this risk. Fentanyl use may cause more serious adverse reactions in patients with chronic obstructive pulmonary disease. PecFent should be administered with extreme caution in patients with increased intracranial pressure. Intravenous fentanyl may produce bradycardia, therefore PecFent should be used with caution in patients with pre-existing bradyarrhythmias; careful consideration should also be given to patients with hypovolaemia and hypotension. PecFent should be administered with caution to patients with hepatic or renal impairment; when administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal impairment

FENTANYL PECTIN NASAL SPRAY

due to alterations in metabolic clearance and plasma proteins. The safety and efficacy of PecFent in children aged below 18 years have not been established. Pharmacodynamic Effects: Analgesic effects in BTP have been demonstrated in RCTs from 5 minutes after dosing, reaching clinically meaningful levels from 10 minutes. Use in 355 patients across 42,227 episodes of BTP for durations of up to 159 days showed infrequent need for additional (rescue) medication (6.0% of episodes) or dose increase (<10% of patients). Side Effects: Typical opioid adverse reactions are to be expected with PecFent, the most serious potentially being respiratory depression, circulatory depression, hypotension and shock; all patients should be monitored for these. Common: disorientation, dysgeusia, dizziness, somnolence, headache, epistaxis, rhinorrhoea, nasal discomfort, vomiting, nausea, constipation and pruritus. Prescribers should consult the SPC in relation to other side effects. Presentation and Cost: One bottle of PecFent 100 or 400 µg/spray (8 sprays) £30.40, one pack (four bottles of PecFent 100 or 400 µg/ spray (32 sprays)) £121.60. Marketing Authorisation Numbers: EU/1/10/644/001-4. Marketing Authorisation Holder: Archimedes Development Ltd, Nottingham, NG7 2TN, UK. Legal Category: CD (Sch2) POM. Date of PI preparation: December 2010. For further information please contact: Archimedes Pharma UK Ltd, 250 South Oak Way, Green Park, Reading, Berkshire, RG2 6UG, UK. References: 1. Portenoy RK, Burton A, Gabrail N et al. Pain 2010;151(3): 617–24. 2. Portenoy R, Raffaeli W, Torres L et al. J Opioid Manag 2010;6(5):319–28. 3. Taylor D, Galan V, Weinstein S et al. J Support Oncol 2010;8:184–190. 4. Fallon M, Gatti A, Davies A et al. Poster 254 presented at the joint 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology; 20-24 Sept 2009, Berlin. 5. PecFent, Summary of Product Characteristics. 6. Fisher A, Watling M, Smith A et al. Int J Clin Pharmacol Ther 2010;48(2):138–45. 7. Portenoy RK, Payne D, Jacobsen P. Pain 1999;81:129-34. 8. Portenoy RK, Bruns D, Shoemaker B et al. J Opioid Manag 2010;6(2):97-108 9. Portenoy RK & Hagen NA. Pain 1990;41:273-81. 10. Watts P & Smith A. Expert Opin Drug Deliv. 2009;6(5):543-552. PEC144. Date of preparation: February 2011

Bringing clinical evidence to practice in primary and secondary care

Contents 4

COVER STORY

Guest Editorial by Dr. Sarah Jarvis FRCGP Diabetes and cardiovascular co-morbidities - the same but different

Volume 5 Issue 1 | February/March 2011 | ISSN 1753-464X

Lipids in and out of context

One in 100 deaths worldwide are ‘due to passive smoking’

Part 2 of reports from the European Association for the Study of Diabetes meeting, Stockholm

Big advances seen in breast cancer survival Depressive symptoms can have important effect on womens’ CV health Immigrant children in USA ‘less likely to have asthma’

Conference reports from: Chicago, Stockholm and Washington

Trial eases concerns about use of drug-eluting stents in large arteries Reports from the American Heart Association meeting, Chicago

Dabigatran better than warfarin in atrial fibrillation study

Reports from ASCO Breast Cancer Symposium 2010

EMA Highlights

The BIG FOUR

World Health Matters

FDA Highlights

View from The Waiting Room

16 One in 100 deaths worldwide are ‘due to passive smoking’

Reports from the European Society of Cardiology meeting, Stockholm

American Society of Clinical Oncology Breast Cancer Symposium, Washington, DC

Emerging uses of EMA approved drugs

Reporting from some of the latest journal articles

6 10

Medical news from around the world

Emerging uses of FDA-approved drugs

E ‘sick’BAY

E V I D E N T I A • V O L U M E 5 • I S S U E 1 • F E B R UA RY / M A R C H 2 0 1 1

Guest editorial by Dr. Sarah Jarvis FRCGP, Richford Gate Medical Practice, London W6

Diabetes and cardiovascular co-morbidities – the same but different

HE HIGH cardiovascular (CV) risk associated with diabetes has long been recognised – in the seminal Framingham study, the risk of MI for men with diabetes was more than doubled compared to those without diabetes, while for women, the comparable risk was more than quadrupled.1 In the last few decades, the common underlying risk factors and metabolic causes of diabetes, hypertension and CV disease have led to diabetes being considered less a metabolic disease and more a cardiometabolic condition.2,3 The NICE guidance on diabetes recommends annual screening for cardiovascular risk and co-morbidities for all patients with Type 2 diabetes.4 In some cases, drug choices and targets are as for nondiabetics with CV co-morbidities. The underlying pathological mechanisms of diabetes, however, mean that in some cases different treatment is called for.

Cardiovascular risk assessment and management As a rule of thumb, every patient with diabetes is at high CV risk until proved otherwise. NICE suggests that the only exceptions are those to whom all the following apply: Normotensive (<140/80mmHg in the absence of antihypertensive therapy) Not overweight Non smoker No high risk lipid profile No personal or family history of CV disease

Contributors: Steve Devrell, Dr. Julie Eastgate, Gary Finnegan, Dr. Sarah Jarvis Peter Mas-Mollinedo, Claire Payne, Bruce Sylvester, Samuel Peters.

ICR

No microalbuminuria The JBS 2 guidelines suggest that all patients with diabetes over 40 should be on statins, as should all those aged 18-39 if they have any of the same risk factors, or retinopathy.5

The JBS 2 guidelines suggest that all patients with diabetes over 40 should be on statins, as should all those aged 18-39 if they have any of the same risk factors, or retinopathy.5

Both sets of guidelines agree that all these patients should be treated to cholesterol targets of below 4mmol/l for total cholesterol and below 2mmol/l for LDL cholesterol. These are, of course, the same targets as those for patients with pre-existing CV disease, whether they have diabetes or not. The increasing downward prescribing pressure from targets for generic simvastatin prescribing in primary care should not deter us from offering these patients high quality care backed up by extensive evidence. Until recently, we have been encouraged to treat the vast majority of patients with diabetes (all those over 50, with blood

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

(UK) PUBLISHING

International Conference Reports

pressure below 145/90 and all those under 50 with any of the CV risk factors above) with aspirin 75mg a day.4 In 2008, however, two studies looking at treatment of diabetics with aspirin failed to show any CV benefit6,7 and in November 2009 a meta-analysis in the BMJ concluded that "a clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved."8 Overall the meta-analysis showed a statistically non-significant 10% reduction in overall CV events (CI 0.81-1.00, P value 0.06), but there were marked gender differences, with a 43% reduction in MI seen among men but no statistically significant reduction in MI among women. The ongoing ACCEPT-D trial9 may provide more answers, but for now the joint American Diabetes Association/American Heart Association/American College of Cardiology have offered pragmatic guidance in the shape of a joint statement. They recommend treatment with aspirin only in men over 50 and women over 60 with one or more additional major CV risk factors.10

Hypertension For patients with diabetes, the NICE guidance sets tighter targets for those with cerebrovascular disease or microvascular damage (<130/80mmHg) compared to those without (<140/80mmHg).4 Treatment should be implemented on the basis of three readings, and readings should be repeated within:

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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 D i r e c t M a r k e t i n g 0 1 2 8 4 7 1 8 9 0 0

E V I D E N T I A • V O L U M E 5 • I S S U E 1 • F E B R UA RY / M A R C H 2 0 1 1

NICE recommends that all patients with diabetes should be given an ACE-inhibitor as first-line treatment – Afro-Caribbeans should be started on dual therapy with ACE inhibitor and diuretic/ calcium channel antagonist.

1 month if BP is higher than 150/90mmHg 2 months if BP is higher than 140/80mmHg 2 months if BP is higher than 130/80mmHg and there is kidney, eye or cerebrovascular damage Once controlled, blood pressure should be monitored every 4-6 months. For patients with diabetes who also have hypertension, choice of blood pressure lowering agent is also different from that for those without diabetes.4,11 For non diabetics, first-line treatment is a thiazide diuretic or a calcium channel blocker for all over 55s or for those of Afro-Caribbean descent.11 Only for under 55s who are not Afro-Caribbean is the first-line choice an ACE inhibitor. NICE recommends that all patients with diabetes should be given an ACE-inhibitor as first-line treatment – Afro-Caribbeans should be started on dual therapy with ACE inhibitor and diuretic/calcium channel antagonist. The only exception is women who might become pregnant, for whom a calcium channel blocker is the first-line choice. The rationale for giving diuretics or calcium channel blockers as first-line therapy to non diabetics over 55 or of Afro-Caribbean origin is that in these patients, hypertension is more likely to be related to sodium retention than to activation of the renin-angiotensin system. Consequently, they tend not to respond as well to ACE inhibitors or Angiotensin Receptor Blockers (ARBs) as monotherapy. For patients with diabetes, however, ACE inhibitors and ARBs both protect against progression of diabetic nephropathy.12,13 The rationale for recommending combination therapy for patients if Afro-Caribbean origin is perhaps because of a desire to offer this renoprotective effect and the lower targets for blood pressure for those with diabetes compared to other patients with uncomplicated hypertension.11

Glycaemic control and CV disease The issue of how low to go in terms of HbA1c is perhaps the most contentious of all with respect to patients with diabetes and cardiovascular co-morbidities. The 10 years follow up of the UKPDS study suggested that tight HbA1c control (median level 7.0%) was associated with a 15% statistically significant risk of MI than conventional control (median HbA1c 7.9%).14 The ADVANCE and VADT studies, on the other hand, showed no cardiovascular benefit from tight glycaemic control15,16 and the ACCORD study showed no cardiovascular benefit and an excess of overall mortality in the tight glycaemic control arm.17 In a 10 year prospective cohort study of 1145 Dutch patients with Type 2 diabetes, Standardised Mortality Ratios for patients with various levels of HbA1c were compared to those of patients with target HbA1cs (6.57%).18 Although SMR for both total and cardiovascular mortality were higher in the total population of patients with HbA1cs outside this range – SMR was 1.86 (95% CI = 1.66 to 2.06) for overall mortality and 2.24 (95% CI = 1.91 to 2.61) for cardiovascular mortality – this ratio was statistically significant only for patients with HbA1cs above 9%, where the hazard ratio (HR) for overall mortality was 2.21 (95% CI = 1.42 to 3.42). Mortality for other groups did not reach statistical significance compared to that of the target group (<6.5%, HR 1.11; 95% CI, 0.71

to 1.74; 7-8%, HR 1.4; 95% CI, 0.99 to 1.97; 8-9%, HR 1.43; 95% CI = 0.97 to 2.10), with similar results for cardiovascular mortality. However, at 1145 patients the study was relatively small and there was a definite trend towards increased mortality for patients in the HbA1c 7-9% groups. In a bigger or longer study, a 40-43% higher mortality rate might have reached statistical significance. The hazard ratio for mortality for HbA1c below 6.5%, on the other hand, was very close to that for target patients at 1.11, suggesting no cardiovascular or mortality benefits for control tighter than an HbA1c of 6.5-7%. Overall, the picture for glycaemic control remains confused. As with aspirin, the American bodies have issued a position statement suggesting that patients with shorter duration of Type 2 diabetes and without established atherosclerosis might reap CV benefit from intensive glycaemic control, but that in those with advanced atherosclerosis, as well as those with frailty, advanced age, history of severe hypoglycaemia or a very long duration of diabetes, the risks of tight glycaemic control may outweigh the benefits.19

Conclusion The high CV risk of all patients with diabetes means that for some parameters, we should largely be treating our patients to the same targets whether they have CV disease or not. However, for those with hypertension our drug choices are influenced by the ‘added bonus benefits’ of some classes of antihypertensive. As for glycaemic control, management should be on a case by case basis – while for some patients tight control might reduce CV morbidity, for those with pre-existing CV disease, overzealous glycaemic control might result in the ultimate ‘hard outcome’ – death. References are available on request.

E V I D E N T I A • V O L U M E 5 • I S S U E 1 • F E B R UA RY / M A R C H 2 0 1 1

European Association for the Study of Diabetes Part 2 of reports from the EASD meeting, Stockholm by Dr. Julie Eastgate

Lipids in and out of context

first study demonstrating that exercise can improve endothelial function in individuals with NAFLD. S Charriere from Lyon described a study to characterise the role of glycosyl phosphatidyl inositol HDL binding protein 1 (GPIHBP1). GPIHBP1 is expressed on the surface of endothelial cells adjacent to adipose tissue and binds lipoprotein lipase, which mediates intravascular lipolysis of triglyceride-rich proteins. A correlation was seen in the expression of GPIHBP1 in subcutaneous and visceral adipose tissue; further GPIHBP1 levels correlated with plasma HDL cholesterol and inversely correlated with triglyceride levels. In patients with Type 2 diabetes, rosiglitazone increased GPIHBP1 expression by 32% (p=0.022). The study showed that GPIHBP1 has a role in lipid metabolism and its levels may be modulated by treatments. L Bilet from Maastricht University described a study to consider the effect of increasing plasma fatty acid levels on cardiac lipid content and energy status. The study used prolonged exercise in fasted, healthy subjects to increase plasma fatty acid levels and demonstrated that 4 hours after exercise their cardiac energy status decreased by 32%, cardiac fat increased from 0.26% to 0.44% (p<0.01) and ejection fraction increased from 59% to 63% (p=0.018). The investigators postulated that the lipotoxicity of circulating fatty acids may compromise energy status and be associated with the development of cardiac dysfunction. B Gaborit from Marseille considered whether ectopic lipid deposition in the cardiac tissue of obese individuals is related to cardiac function. In obese individuals there is a generalised increase in adipose tissue mass and subsequent ectopic deposition in other organs. In the heart fat deposits as myocardial adipose around the arteries. Assessment of myocardial triglyceride The study implemented a 16-week supervised, exercise regimen in 6 sedentary NAFLD patients. content and epicardial fat volume SESSION AT the 46th Annual Meeting of the European Association for the Study of Diabetes considered ‘Lipids in and out of context’, with a number of brief oral presentations detailing recent study findings. C Pugh from Liverpool described the use of exercise to reduce liver fat in individuals with non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD are often obese, have impaired glucose regulation and cardiovascular risk factors, and early signs of cardiovascular disease. The study implemented a 16-week supervised, exercise regimen in 6 sedentary NAFLD patients, which resulted in: a significant improvement in cardiorespiratory fitness; a small but significant reduction in body mass index; significant reductions in aspartate and alanine transaminase and hepatic fat levels; and a 3% improvement in flow-mediated dilatation of the brachial artery (7.3% vs. 3.8%). This is the

E V I D E N T I A • V O L U M E 5 • I S S U E 1 • F E B R UA RY / M A R C H 2 0 1 1

showed that those with diabetes had more epicardial fat and myocardial triglyceride than obese individuals, and that both groups had significantly more than lean subjects; epicardial fat volume correlated negatively with thigh circumference/body mass index ratio, suggesting a relationship with reduced subcutaneous deposition. Myocardial triglyceride content was independently associated with various indicators of cardiac function, suggesting that lipid oversupply to myocytes may result in lipotoxic injury.

The investigators postulated that the lipotoxicity of circulating fatty acids may compromise energy status and be associated with the development of cardiac dysfunction.

I Lingvay from Texas University assessed pancreatic triglyceride and total pancreatic fat levels in individuals with and without diabetes. Pancreatic triglyceride levels increased with body mass index and, in non-diabetic subjects, was higher in those with impaired glucose tolerance/fasting glucose; pancreatic triglyceride levels were higher in those with diabetes and related to the amount of visceral fat but not the amount of subcutaneous or hepatic fat. Overall 53% of β-cell function remained in those with normal glucose tolerance, 31% remained in those with impaired glucose tolerance/fasting glucose, and 16% remained in those with Type 2 diabetes; the data indicated a statistically significant association between pancreatic triglyceride levels and β-cell function and the authors proposed that they contribute to the development of diabetes.

Poster sessions at EASD Two studies on the use of pioglitazone in patients with Type 2 diabetes.

POSTER SESSION at the 46th Annual Meeting of the EASD considered research into the findings of two studies on the use of pioglitazone in patients with Type 2 diabetes. The PIOcomb study considered the comparative efficacy and safety of three combination therapy regimens, comprising: pioglitazone and insulin, metformin and insulin, and the triple agent regimen of pioglitazone, metformin and insulin. Interim analysis of the double-blind, multi-centre study considered 78 patients with Type 2 diabetes who were previously receiving insulin. Treatment was guided by the goal of achieving a normal fasting glucose level. After 6 months on study treatment haemoglobin A1c (HbA1c ) level remained stable for the dual combination therapy groups but decreased significantly for patients receiving the triple combination (from 7.3% to 6.8%). The daily insulin dose required increased significantly from 37 to 41IU for patients receiving metformin and insulin and decreased significantly for those receiving pioglitazone and insulin (from 37 to 29IU) and triple combination therapy (from 36 to 28IU). The use of pioglitazone in a combination regimen improved insulin sensitivity and β-cell

function. Patients receiving triple combination therapy experienced a lower incidence of oedema and did not see a notable increase in body weight. A second aspect of PIOcomb was to consider the effect of combination therapy on chronic systemic inflammation, as an indication that the pathophysiological processes associated with the progression of Type 2 diabetes can be modulated by treatment. In particular, reducing chronic systemic inflammation may be able to impact on the development of the macrovascular complications associated with Type 2 diabetes. Treatment with pioglitazone was associated with a consistent statistically-significant reduction in the levels of C-reactive protein and E-selectin. The levels of other inflammatory markers showed either a significant improvement in just one of the pioglitazone treatment groups or a numerical tendency for improvement that did not reach statistical significance. No tendency for a reduction in inflammatory marker levels was seen for patients receiving metformin and insulin. The PIOren study considered the use of pioglitazone as add-on therapy to insulin in patients with Type 2 diabetes who require haemodialysis. In patients with clinically-

significant kidney disease insulin pharmacokinetics are altered and vascular insulin resistance is common, which can compromise therapy. Interim analysis of the use of the insulin-sensitizer in this randomised, double-blind, placebocontrolled trial showed that pioglitazone was able to effect a 32% reduction in the dose of insulin required from baseline (p<0.05) and achieve clinically-relevant reductions in HbA1c (0.62%, p<0.01), fasting plasma glucose (56mg/dL, p<0.05) and triglyceride levels (111mg/dL, p<0.05) and an increase in adiponectin level (6.9mg/L). No change in ultrafiltrate volume was associated with pioglitazone treatment. Early results from these studies indicate that aggressive combination therapy regimens that include pioglitazone are effective at improving glycaemic control and reducing insulin requirement; pioglitazone may have the added advantages of improving β-cell function and reducing chronic systemic inflammation. These characteristics indicate the potential for such regimens to modify the course of Type 2 diabetes, reduce the likelihood of patients developing diabetic complications and improve prognosis in those with late stage disease.

The use of sodium-glucose transporter-2 (SGLT-2) inhibitors, with interest primarily focussing on dapagliflozin and canagliflozin.

POSTER SESSION at the 46th Annual Meeting of the EASD considered the use of sodiumglucose transporter-2 (SGLT-2) inhibitors, with interest primarily focussing on dapagliflozin and canagliflozin. Posters considering dapagliflozin focussed on data from randomised, placebo-controlled trials in the Phase III development programme, of use as mono- and combination therapy across various Type 2 diabetes stages. In the monotherapy trial dapagliflozin at doses of 5mg and 10mg achieved statistically significant reductions in haemoglobin A1c (HbA1c) (0.77% and 0.89% reductions for the 5mg and

10mg doses versus a 0.23% reduction with placebo) and fasting plasma glucose (24.1mg/dL and 28.8mg/dL reductions respectively versus 4.1mg/dL). Body weight reductions were also apparent. When dapagliflozin was used as add-on therapy with glimepiride or metformin statistically significant reductions in HbA1c and plasma glucose levels and body weight were apparent. In patients receiving insulin therapy and dapagliflozin (with or without oral anti-diabetic agents) statistically significant benefits were seen after 24 weeks of treatment across all dapagliflozin doses for HbA1c, fasting plasma glucose, body weight reduction, and the ability to maintain the

baseline insulin dose; benefits were consistent through the 48 week extension phase of the trial. Across the development programme dapagliflozin was also associated with a numerical reduction in systolic blood pressure when compared with placebo. Dapagliflozin had a favourable safety profile but showed a slightly higher incidence of urinary and/or genital tract infection (and occasional cases of pyelonephritis). These findings indicate that dapagliflozin is able to improve glycaemic control for patients with all stages of Type 2 diabetes and has the added benefit of promoting weight loss and blood pressure lowering. CONTINUED ON PAGE 8 >

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EASD Part 2 of reports from the EASD meeting, Stockholm

Poster sessions at EASD < CONTINUED FROM PAGE 7

Posters considering canagliflozin described data from three randomised, placebo-controlled monotherapy trials. In one trial canagliflozin was administered to obese subjects who were also required to adhere to a fixed weight-maintaining diet. Canagliflozin administration significantly increased urinary glucose in a dose-dependent manner; patients with impaired fasting glucose or impaired glucose tolerance at the start of the study achieved a significant reduction in their 24-hour mean plasma glucose (from 6.1mmol/L to 5.6mmol/L). In addition, the body weight of study participants decreased during the study without changes in appetite or satiety. In a Phase Ib study in patients with Type 2

These findings indicate that dapagliflozin is able to improve glycaemic control for patients with all stages of Type 2 diabetes and has the added benefit of promoting weight loss and blood pressure lowering. diabetes, canagliflozin effected a dose-dependent increase in urinary glucose which was associated with reductions in 24-hour mean plasma, postprandial, and fasting plasma glucose. Correlation between insulin secretion rate and plasma glucose level showed that β-cell function improved at canagliflozin doses of 100mg or greater. A larger study considered canagliflozin as add-on therapy for Type 2 diabetes patients who were not achieving glycaemic control with metfomin. In this group canagliflozin achieved significant reductions in HbA1c level, fasting plasma glucose, weight loss and improved β-cell function. The data showed that individuals with Type 2 diabetes often have an elevated renal glucose threshold that can be reduced by canagliflozin. In some studies canagliflozin appeared to be associated with skin adverse events or genital infection. The beneficial effects of canagliflozin on glycaemic control and body weight, and the favourable safety/tolerability profile have led to the selection of 100mg and 300mg once-daily dosing for the ongoing Phase III study programme.

ACTOS® PRESCRIBING INFORMATION pioglitazone (Refer to Summary of Product Characteristics before prescribing) Actos® tablets (pioglitazone).Presentations: Actos 15mg tablets containing 15mg pioglitazone as hydrochloride - blister packs of 28 EU/1/00/150/001 £25.83. Actos 30mg tablets containing 30mg pioglitazone as hydrochloride - blister packs of 28 EU/1/00/150/004 £35.89. Actos 45mg tablets containing 45mg pioglitazone as hydrochloride - blister packs of 28 EU/1/00/150/012 £39.55. Indications: Monotherapy treatment of Type 2 diabetes mellitus in patients inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance. As dual oral therapy in patients with insufficient glycaemic control despite maximal tolerated dose of oral monotherapy, in combination with either metformin (particularly in overweight patients) or a sulphonylurea (in patients for whom metformin is not tolerated or contraindicated). As triple oral therapy with metformin and a sulphonylurea in patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy. In combination with insulin in patients with insufficient glycaemic control on insulin for whom metformin is not tolerated or contraindicated. Dosage: 15mg or 30mg once daily with or without food. Dose may be increased in increments up to 45mg once daily. In combination therapy with insulin the current insulin dose can be continued. If patients report hypoglycaemia, the dose of insulin should be decreased. Elderly & renal impairment (Cl creatinine >4 ml/min): No dosage adjustment required. No information is available from dialysed patients therefore pioglitazone should not be used. Children and adolescents (under 18 years): Not recommended. Contraindications: Hepatic impairment. Hypersensitivity. Cardiac failure or history of cardiac failure (NYHA stages I to IV). Diabetic ketoacidosis. Warnings and precautions: Can cause fluid retention, which may exacerbate or precipitate heart failure. Observe patients for signs and symptoms of heart failure, weight gain or oedema particularly those with reduced cardiac reserve or on insulin. Discontinue pioglitazone if deterioration in cardiac status occurs. For patients with at least one risk factor for congestive heart failure, start therapy with the lowest dose of pioglitazone and increase gradually. Concomitant insulin administration may increase the risk of oedema. Check liver enzymes before starting treatment. Following initiation it is recommended that liver enzymes be monitored periodically based on clinical judgement. Do not start treatment in patients with increased baseline liver enzyme levels (ALT >2.5 x upper limit of normal [ULN]). If ALT levels increase to 3 x ULN, reassess as soon as possible. If ALT levels remain >3 x ULN or jaundice is observed, discontinue therapy. If symptoms suggest hepatic dysfunction, check liver enzymes. Advise patients to adhere strictly to a calorie-controlled diet and monitor weight. In some cases, an increase in weight may be a symptom of cardiac failure. Small reductions in haemoglobin and haematocrit, consistent with haemodilution have been noted. Treatment in patients with polycystic ovarian syndrome may result in ovulation. If a patient wishes to become pregnant or if pregnancy occurs, discontinue treatment. An increased incidence in bone fractures in women has been observed in a pooled analysis of safety data involving pioglitazone treatment. The risk of fractures should be considered in the long term care of women treated with pioglitazone. Interactions: Use with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Monitor glycaemic control. Pregnancy and lactation: Do not use. Potential risk unknown. Undesirable effects: Suspected adverse reactions reported as more than an isolated case in double-blind studies listed below. Very common: >10%, common: 1-10%, uncommon: 0.1-1%, rare: 0.01-0.1% and very rare: <0.01%. In monotherapy: Common: visual disturbance, upper respiratory tract infection, weight increased, hypoaesthesia. Uncommon: sinusitis, insomnia. With metformin: Common: anaemia, weight increased, headache, visual disturbance, arthralgia, haematuria, erectile dysfunction. Uncommon: flatulence. With sulphonylurea: Common: weight increased, dizziness, flatulence. Uncommon: glycosuria, hypoglycaemia, increased lactic dehydrogenase, appetite increased, headache, vertigo, visual disturbance, sweating, proteinuria, fatigue. With metformin and sulphonylurea: Very common: hypoglycaemia. Common: weight increased, blood creatinine phosphokinase increased, arthralgia. With insulin: Very common: oedema. Common: hypoglycaemia, bronchitis, weight increase, back pain, arthralgia, dyspnoea, heart failure. Oedema reported in 6-9% of patients on pioglitazone over one year, compared to 2-5% in the comparator groups (metformin and sulphonylurea). Oedema was generally mild-moderate and usually did not require discontinuation of treatment. In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were seen, with small, but not clinically significant, increases in LDL-cholesterol levels. In clinical trials the incidence of elevations of ALT >3 x ULN was equal to placebo. In an outcome study of patients with prior major macrovascular disease, the incidence of heart failure was 1.6% higher with pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience, although causal relationship has not been established. There have been a small number of post marketing reports of macular oedema. Be alert for disturbances in visual acuity. An increased incidence in bone fractures in women has been observed in a pooled analysis of safety data involving pioglitazone treatment.

Please refer to the summary of product characteristics for details on the full side-effect profile of Actos. Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should alsobe reported to Takeda UK Ltd.

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

PI Date Code: Jan 2010. Legal category: POM. MARKETING AUTHORISATION HOLDER: Takeda Global R & D Centre (Europe) Ltd. Takeda UK Ltd. is responsible for the sale and supply of ACTOS in the UK. Actos is a registered trademark owned by Takeda Pharmaceutical Company Ltd. For further information contact: Takeda UK Ltd. Takeda House, Mercury Park, Wycombe Lane, Wooburn Green, High Wycombe, Bucks HP10 0HH. Tel: 01628-537900, Fax: 01628-526617. AC091241 References: 1. Intellectual Property Office: http://www.ipo.gov.uk. Last accessed February 2011. 2. Matthews DR et al. Diabetes Metab Res Rev 2005; 21: 167-174. 3. Campbell IW. Br J Diabetes Vasc Dis 2009; 9: 53-63. 4. Tan MH et al. Diabetes Care 2005; 28: 500-544. 5. Data on File. Takeda UK Ltd. AC100603. Date of preparation November 2009. Date of preparation: February 2011 Code: AC110184g

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www.T2Dresource.co.uk

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Plan for the future, now

patients s e t e b a in, e 2 di For Typ lled on metform rs e o uncontr glitazone) deliv io ble Actos (p ional and dura d.2-4 t i the add ontrol they nee ic c glycaem ed nt expir e t a p s o g The Act 2011, so usin h ot ary in Janu now makes b .5 e nse zon pioglita nd financial se a clinical

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American Heart Association Reports from the AHA meeting, Chicago by Thomas R. Collins

Trial eases concerns about use of drug-eluting stents in large arteries

RUG-ELUTING stents were just as safe as stents that are not drugcoated in patients with narrowed large arteries, researchers said at the 2010 American Heart Association Scientific Sessions 2010. The conclusions of the so-called BASKETPROVE trial - which tested two kinds of drugeluting stents against bare-metal stents - may open a new option for cardiovascular patients and their physicians, alleviating a concern about drug-eluting stents in large arteries that stemmed from the findings of a previous trial. “In contemporary stenting of large coronary arteries, late safety problems of drug-eluting stents could no longer be confirmed - there was even a trend in the opposite direction,” said Christoph Kaiser, a study co-author and Assistant Professor of Cardiology and head of interventional cardiology at Switzerland’s University Hospital Basel. “Both drug-eluting stents showed superior efficacy compared with bare-metal stents,” with a reduction in revascularisation rate of more than 50%. In the previous trial by Kaiser’s research group, the BASKET-LATE trial,1 a higher

incidence of “late” cardiovascular death and heart attack, months or years after stent implantation, was found in those treated with drug-eluting stents compared to bare-metal stents. The study was a single-centre trial of 816 patients.

“Since bare-metal stents and drug-eluting stents showed similar death and MI rates, bare-metal stents may still be used, but with a higher TVR (target vessel revascularisation) rate.”

But the conclusion stemmed from a retrospective analysis in an underpowered trial, and therefore was “highly questionable,” Dr Kaiser said. In the BASKET-PROVE trial, 2,314 patients were randomised to receive a drug-eluting stent - coated with either everolimus or sirolimus - or a baremetal stent in a large artery, considered to be those requiring stents of 3mm or bigger. Participants were enrolled from 2007 to 2008. After two years, the rate of cardiac death or heart attack was 2.7% for the sirolimus-coated stents, 3.3% for the everolimus-coated stents and 4.8% for the bare-metal stents. “The findings of

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BASKET-PROVE imply that in patients in need of large coronary artery stenting, drug-eluting stents may be used without evidence of increased late cardiac events or late stent thrombosis,” Dr. Kaiser said. “Since baremetal stents and drug-eluting stents showed similar death and MI rates, bare-metal stents may still be used, but with a higher TVR (target vessel revascularisation) rate.” Doctors should also feel comfortable using either first-generation sirolimus- or second-generation everolimus-coated stents, since there was no difference in their results, Dr. Kaiser said. Marco Valgimigli, MD PhD, Chair of Cardiology at the University of Ferrara in Italy, said the results from BASKET-PROVE cannot be considered “conclusive” but are “highly reassuring.” Problems with drug-eluting stents might have been seen in the first BASKET study in part because, in the trial, those with stents implanted into larger arteries were young with a lower diabetes rate, two traits that have been found to have a protective effect against very late stent thrombosis. He also said that the larger arteries may have given rise to improper stent placement in those patients. It is also possible that the first BASKET trial’s conclusion was just a “chance” finding. BASKET-PROVE, though, “cannot rule out the existence of a smaller than anticipated difference in events,” he said. On the other hand, “the safety issue which has been noted in BASKET-LATE has not been confirmed here and indeed the composite of CD/MI trended even in favour of drugeluting stents.” The comparisons between everolimus- and sirolimus-eluting stents, he cautioned, should be viewed as “purely exploratory.” Reference: 1. Pfisterer P, Brunner-La Rocca H, Rickenbacher P, Hunziker P, Mueller C et al. Eur Heart J 2009; 30(1): 16-24. doi: 10.1093/eurheartj/ehn516

Review of studies on women with heart disease reveals interesting trends

EPRESSIVE SYMPTOMS and other psychological traits can have important effects on the cardiovascular health of women, and women score worse than men on quality of life tests after cardiovascular events, a researcher said at the 2010 AHA Scientific Sessions. A review of 199 studies of outcomes of women who have heart disease in areas of readmissions to the hospital, mortality and quality of life revealed interesting trends, while also showing that research into women’s cardiovascular issues could be honed for better insights, said Colleen Norris, RN PhD, Associate Professor of Nursing at the University of Alberta. Those studies were identified, in an effort led by Dr Norris, after a comprehensive search of more than 3,400 studies. The seven studies that were identified on hospital readmissions found a few themes, Dr. Norris said. “Higher depression in women equals a higher rehospitalisation rate,” she said. “Cardiac rehab prevents readmissions in both sexes. Women with normal coronaries… were four times more likely to be readmitted to the hospital.” A total of 138 studies examined mortality in women with heart disease. “The overall theme was that women (receiving coronary artery bypass graft surgery) are older, more likely to have diabetes, more likely to have elevated BP (blood pressure), hyperlipidaemic and less likely to be a smoker. And sex is not an independent predictor of mortality following adjustment,” Dr. Norris said. Studies on mortality that included only women found that hypertension was a significant contributor to mortality, particularly from stroke and coronary heart disease. They also found that depressive symptoms manifested in the body - but not those that were cognitive - were associated with an increased risk of cardiovascular disease mortality.

And a six-month history of full-blown panic attacks was an independent predictor of coronary heart disease and death. The studies also found that using antidepressants and anti-anxiety drugs gave women a higher risk for cardiovascular events

“Cardiac rehab prevents readmissions in both sexes. Women with normal coronaries… were four times more likely to be readmitted to the hospital.”

their heart disease as influencing changes in their daily lives. Those studies also found that previously healthy obese women with a risk profile for cardiovascular disease seemed to have a high risk of diabetes, as well as for psychological and psychosocial problems. After acute myocardial infarction, they concluded, women reported poor satisfaction with life and experienced depression - although religion, family and friends provided strength and comfort. Dr. Norris said that looking at “gender roles,” rather than just “sex” - or, more specifically, how individuals respond to their gender roles - might be worthwhile since it is apparent that how they respond affects their health. “Qualifying the impact of the concordance or dissonance with gender stereotypes and using ‘gender role’ as an independent variable,” she said, “may provide future directions for those of us trying to understand and improve the outcomes of women with heart disease.”

and that group-based psychological intervention programmes could help prolong life for women with coronary heart disease after adjustments were made for other risk factors. Fifty-four studies were found that involved the quality of life of women with heart disease. Overall, the studies found that women with coronary artery disease score worse in health-related quality of life compared to men, have higher levels of stress than men, and that after acute myocardial infarction report lower satisfaction with life and worse mental health. The studies involving just women found that depressive symptoms were the strongest Group-based psychological intervention programmes could predictor of HRQOL scores help prolong life for women with coronary heart disease and that women perceived after adjustments were made for other risk factors. E V I D E N T I A • V O L U M E 5 • I S S U E 1 • F E B R UA RY / M A R C H 2 0 1 1

Cardiology study

HDL function tied to cardio risk

MEASURE OF the ability of HDL to remove cholesterol from macrophages predicted the likelihood that an individual undergoing cardiac catheterisation had coronary artery disease, a cross-sectional study showed. As cholesterol efflux capacity increased, the odds of coronary disease dropped, an effect independent of HDL cholesterol (P=0.002), according to Daniel Rader, MD, of the University

"These observations suggest that HDL efflux capacity is a measure of HDL function that is relevant to the pathogenesis of atherosclerosis. These observations also support the proposal that dysfunctional HDL contributes to the risk of coronary disease."

of Pennsylvania in Philadelphia, and colleagues. Compared with patients with the lowest efflux capacity, those with the highest had a 52% reduced likelihood of having coronary disease after adjustment for cardiovascular risk factors and HDL cholesterol level (OR 0.48, 95% CI 0.30 to 0.78), the researchers reported in the New England Journal of Medicine. Also, in a group of healthy volunteers, cholesterol efflux capacity was inversely associated with carotid intima-media thickness, even after adjustment for HDL cholesterol and apolipoprotein A-I levels (P<0.05). "Our demonstration that cholesterol efflux

capacity is associated with atherosclerosis in humans helps support the use of this measure in guiding the development of new HDLtargeted therapies for humans," Rader and his colleagues wrote. All of the participants gave blood, and the researchers used an In an accompanying assay to quantify cholesterol efflux capacity. editorial, Jay Heinecke, MD, of the University of In the healthy volunteers, lower efflux Washington in Seattle, wrote, "These capacity was associated with increased carotid observations suggest that HDL efflux capacity intima-media thickness both before and after is a measure of HDL function that is relevant to adjustment for cardiovascular risk factors, HDL the pathogenesis of atherosclerosis. These cholesterol level, and apolipoprotein A-I. observations also support the proposal that Efflux capacity was also a strong inverse dysfunctional HDL contributes to the risk of predictor of coronary artery disease, with an coronary disease." odds ratio per standard-deviation increase in Although HDL cholesterol levels are capacity of 0.70 (95% CI 0.59 to 0.83) after inversely related to risk of coronary disease, adjustment for cardiovascular risk factors. studies have questioned whether raising HDL Additional adjustment for HDL cholesterol and cholesterol with drugs is beneficial. apolipoprotein A-I did not substantially The function of HDL cholesterol may be change the results. more important than its level, according to the The researchers also performed the assay on researchers. HDL cholesterol may provide samples from 39 patients with metabolic cardioprotection by promoting reverse syndrome who participated in a placebocholesterol transport by accepting cholesterol controlled trial of pioglitazone and from 99 from macrophages loaded with lipids, thereby patients with hypercholesterolaemia who decreasing inflammation. participated in a placebo-controlled trial of To assess the relationship of cholesterol statin therapy. efflux capacity with atherosclerosis, Rader and Cholesterol efflux capacity was enhanced his colleagues recruited 203 healthy by pioglitazone but not by statin therapy, volunteers to have carotid artery intima-media which "is consistent with the concept that thickness measured by ultrasound, and also statins most likely exert therapeutic benefit by recruited 793 patients who were undergoing means of a mechanism that is distinct from the cardiac catheterisation. Of the latter group, promotion of cholesterol efflux," according to 442 had angiographically confirmed coronary the researchers. disease and 351 had no evidence of disease. They acknowledged that their study was All of the participants gave blood, and the limited by the cross-sectional design. researchers used an assay to quantify "Another limitation is that although our cholesterol efflux capacity. assessment of cholesterol efflux capacity There were significant correlations between reflects the ability to mobilise free cholesterol cholesterol efflux capacity and levels of both from macrophages, it does not capture HDL cholesterol and apolipoprotein A-I in all variation in the reverse-cholesterol-transport participants (P<0.0001).

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American Heart Association

End-stage renal disease involves different risk factors for CV events

pathway in terms of cellular components (i.e., the hydrolysis of cholesteryl esters and the status of endogenous macrophage cholesterol transporters) or terminal components (i.e., uptake into the liver and biliary excretion)," they wrote. The study was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) and the National Center for Research Resources, and by a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation. Rader's co-authors reported support from a medical student research fellowship from the Howard Hughes Medical Institute and a K23 award from the NHLBI. Rader reported that his institution received a grant from the NIH. He also reported being a founder of VascularStrategies, which provides services related to the development of new therapeutics for atherosclerotic cardiovascular disease, including, but not limited to, assessment of reverse cholesterol transport, cholesterol efflux, and HDL function. Heinecke reported receiving grants from the NIH and Merck and serving as a consultant for Merck, Schering-Plough, Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and Corcept. He has received payment for lectures from Merck and owns stock or stock options in Insilicos. Heinecke and a colleague, along with the University of Washington, hold a patent that relates to diagnostic tests for measuring the quantity of one or more HDL oxidation products, which may be useful in evaluating the risk for developing cardiovascular disease. The Cleveland Heart Labs has a licensing agreement with the University of Washington based on the patent. Reference: Khera A, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011; 364: 127-135.

IDNEY DISEASE is a strong independent risk factor for cardiovascular events, but the factors associated with cardiovascular risk change as kidney disease becomes more advanced, according to a Swedish expert who spoke at the 2010 AHA Scientific Sessions. “A different metabolic syndrome can be identified in advanced renal failure,” said Bengt Fellstrom, MD PhD, Professor of Nephrology at Uppsala University Hospital. “This is where the CV risk increases with low BMI, low total cholesterol and low LDL cholesterol and high pulse pressure.” Both heart disease and kidney disease are critical to many diabetic patients. Those with diabetes are twice as likely as those without it to develop heart disease, according to the American Diabetes Association. And about 30% of people with Type 1 diabetes will develop kidney disease, and 10% to 40% of those with Type 3 diabetes will develop kidney disease, according to the National Kidney Foundation in the U.S. According to a 2004 study that examined 1.1 million adults in an insurance database, those with a glomerular filtration rate of 60 or greater suffered 2.11 cardiovascular events per 100 person years, while those with a GFR of less than 15 suffered 36.6 cardiovascular events for every 100 person years.1 A study on which Dr. Fellstrom worked showed that cardiovascular events and deaths tend to skyrocket as creatinine levels rise.2 Other studies have shown that cardiovascular mortality is considerably higher among those who have had kidney transplants, and that mortality is “massively” increased in dialysis patients as compared to the general population, Dr. Fellstrom said. In the ALERT trial, a study of fluvastatin in kidney transplant patients on which Dr. Fellstrom worked, metabolic syndrome was found to increase the chance of cardiac death or heart attack by 80%. Researchers defined metabolic syndrome as having three or more of: a BMI of 30 or more; serum triglycerides of 1.7mmol/L or more; blood

pressure of greater than 130/85; fasting plasma glucose of at least 110mg/dL; or HDL of less than 1.03 for males and less than 1.29 for females. In the study, diabetes was found to increase the chances of cardiac death or myocardial infarction by 71%. For those with end-stage renal disease, a different picture emerges, Dr. Fellstrom said. The AURORA trial, a study on rosuvastatin and cardiovascular events in dialysis patients, researchers found that diabetes came with a 78% increase in risk of a major adverse cardiovascular event.3

Both heart disease and kidney disease are critical to many diabetic patients.

But total cholesterol level had a relative risk measurement of 0.94, meaning that higher cholesterol actually meant a lower risk. Researchers also found that BMI did not have a significant effect on risk of a major adverse cardiovascular event. The main reasons for this change for endstage renal disease, Dr. Fellstrom explained, is that these patients are at a greater risk for malnutrition and inflammation. “These patients are suffering from extremely high risk of cardiovascular complications and the risk factors are different,” he said. “Total cholesterol, LDL cholesterol, seem, in several investigations, to be a reverse risk in dialysis patients. The lower the risk, the higher the risk.” References: 1. Go A, Chertow M, Fan D, McCulloch C, Hsu C-Y. N Engl J Med 2004; 351: 1296-1305 2. Fellström B, Jardine A, Soveri I, Cole E, Neumayer H et al. Am J Transplant 2005; 5: 1986-91 3. Bengt C, Fellström B, Jardine A, Schmieder R, Holdass H et al. N Engl J Med 2009; 360: 1395-1407

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European Society of Cardiology Reports from the ESC meeting, Stockholm by Samuel Peters

Dabigatran better than warfarin in atrial fibrillation study

HIGH DOSE of dabigatran, was more effective in preventing strokes in high-risk patients than warfarin. The results led some practitioners to suggest that dabigatran could replace warfarin as the standard treatment for atrial fibrillation. In an 18,000-patient, phase III trial, those randomised to 150mg of dabigatran twice a day had significantly lower rates of both haemorrhagic stroke and ischaemic stroke than patients taking warfarin, according to Michael Ezekowitz, MB,ChB, DPhil, of the Lankenau Institute for Medical Research and Heart Center in Wynnewood, PA., and colleagues. But at the lower dose of 110mg twice a day, the drug was comparable to warfarin, he reported. The findings of the RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) were simultaneously published in the New England Journal of Medicine and presented at an ESC HotLine session by Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, lead author of the NEJM paper. The rate of major bleeding was 2.71% per year among patients who received low dose dabigatran, versus 3.36% in the warfarin arm (P=0.003). "From my perspective, it is an amazing result. The 150mg dose was unequivocally superior to warfarin without compromising, without major bleeding," Ezekowitz said. He said that if dabigatran were to be approved, "it will become the new standard against which every other [anticoagulant] will need to be compared." Ezekowitz and colleagues concluded that the "net clinical benefit outcome, which is a measure of overall benefit and risk, was similar between the two doses of dabigatran, owing to the lower risk of

ischaemia with the 150mg dose and the lower risk of haemorrhage with the 110mg dose." This suggested that the dose could be tailored to suit the individual patient risk profile.

“From my perspective, it is an amazing result. The 150mg dose was unequivocally superior to warfarin without compromising, without major bleeding."

Ischaemic stroke occurred in 134 patients taking high dose dabigatran versus 199 patients receiving warfarin therapy (P<0.001), a 34% reduction in relative risk compared with warfarin. High dose dabigatran was associated with a haemorrhagic stroke rate of 0.10% per year versus 0.38% for warfarin (P<0.001). "To prevent one nonhaemorrhagic stroke, the number of patients who would need to be treated (NNT) with dabigatran at a dose of

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150mg twice daily, rather than warfarin, is approximately 357," Brian F. Gage, MD, of Washington University in St. Louis, wrote in an accompanying editorial. Proper management of warfarin remains a challenge, because patients must undergo regular monitoring of international normalised ratio (INR) to be sure the drug is correctly dosed. A 2001 Cochrane review by Segal et al found that the NNT to prevent stroke with warfarin was 18, but that was compared with placebo. This may explain why the NNT to prevent stroke with dabigatran versus warfarin was so high: warfarin, when properly managed has good efficacy. Connolly said the MI finding was unexpected and will require "additional analysis," but he theorised that it was more likely a reflection of the "benefit of warfarin in reducing MI" than a safety signal for dabigatran. He also said that current plans are to seek approval for the drug at both the 110mg and the 150mg bid doses. A potentially greater obstacle than MI risk, which was slight regardless of treatment, was the rate of dyspepsia with dabigatran, which was twice the rate as in the warfarin group (11.3% versus 5.8%, P<0.001). Dyspepsia was the main driver of a significantly higher second year dropout rate in the dabigatran arm (21% versus 16.6%, P<0.001). The trial, which was designed as a noninferiority study, enrolled 18,113 patients who had documented atrial fibrillation and at least one additional stroke risk factor - history of stroke, left ventricular ejection fraction less than 40%, New York Heart Association Class II or higher within six months before screening, age 75 or older, or ages 65 to 74 plus diabetes, hypertension, or coronary artery disease. Patients were randomised in a

The RELY trial

TROKE INCIDENCE increases with age. Atrial fibrillation (AF) is an important risk factor for ischaemic stroke and its incidence also increases with age. However oral anticoagulant therapy tends to be underused in the elderly population, mainly due to the difficulties in prescribing warfarin. Atrial fibrillation (AF) is responsible for one-sixth of all strokes. Although warfarin reduces stroke by 64% in patients with AF, it causes significant increases in intracranial and other haemorrhages. Because of the need for constant monitoring of warfarin, only 50% of eligible patients receive it, and prothrombin times within the therapeutic range, an International Normalised Ratio (INR) of two to three, are controlled in only about half of those receiving it. In the RELY study (Randomised Evaluation of Long-Term anticoagulation Therapy), investigators enrolled 18,113 patients with nonvalvular AF and at least one other risk factor for stroke. Patients were randomly

blinded fashion to 110mg dabigatran (N=6,015) or 150mg dabigatran (N=6,076) or unblinded, dose-adjusted warfarin (6,022). The median duration of follow-up was two years. Among the findings: There were 80 disabling or fatal strokes in the dabigatran 150mg arm, versus 118 in the warfarin arm (P=0.005) There were 274 deaths from vascular causes in the high dose dabigatran arm, versus 317 in the warfarin arm (P=0.04) The hospitalisation rate was 20.2% with 150mg dabigatran, versus 20.8% for warfarin (P=0.003) The overall mortality rate was 4.13% in the warfarin group, versus 3.75% in the highdose dabigatran arm, which was not significant (P=0.051)

assigned to three groups of about 6,000 each. They received open-label warfarin, adjusted to an INR of two to three; dabigatran 110mg twice daily; or dabigatran 150mg twice daily. Median follow-up was two years. Dabigatran etexilate is an anticoagulant and a direct thrombin inhibitor (DTI). In a non-inferiority analysis, both dabigatran doses were non-inferior to warfarin for the primary endpoint of reducing stroke (P < 0.001). At the 150mg twice-daily

The authors noted that use of open-label warfarin "could have introduced a bias in the reporting or adjudication of events," but they said this potential for bias was reduced by the use of "blinded evaluation of outcome events." As evidence they offered the "unexpectedly different rates of myocardial infarction and gastrointestinal bleeding among the three treatment groups." Disclosure: RE-LY was funded by Boehringer Ingelheim, developer of dabigatran. Connolly reported receiving consulting fees, lecture fees, and grant support from Boehringer Ingelheim. References: Connolly, SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; Article was published online Aug. 30, 2009. Gage BF. Can we rely on RE-LY? N Engl J Med 2009; Article was published online Aug. 30, 2009.

dose, dabigatran was superior to warfarin in reducing the incidence of stroke and systemic embolism by 34%. The relative risk (RR) was 0.66, with a 95% confidence interval (CI) of 0.53 to 0.82 (P < 0.001). Major bleeding rates with dabigatran 150mg twice daily (3.11% of patients per year) were similar to those with warfarin (3.36% of patients per year) (P = 0.31). The rate of major bleeding associated with dabigatran 110mg twice daily was 20% lower than that of warfarin (2.71% per year; P = 0.003). For the 150mg and 110mg twice-daily dabigatran doses, compared with warfarin, significant RR reductions were found for haemorrhagic stroke (74% and 69%, respectively; P < 0.001 for both). The vascular mortality rate was also lower for dabigatran 150mg twice daily (RR reduction, 15%; P = 0.04). Importantly, abnormal liver function, defined as alanine transaminase or aspartate transaminase levels of more than three times the upper limit of normal (ULN) and concurrent bilirubin levels of more than two times the ULN, was not more frequent with dabigatran. After noting that dabigatran reduced strokes and that patients needed less monitoring and no pharmacogenomic studies, many practitioners predicted that dabigatran therapy could be the stimulus to a paradigm change in anti-thrombotic management of atrial fibrillation.

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Reports from ASCO Breast Cancer Symposium 2010 American Society of Clinical Oncology Breast Cancer Symposium, Washington, DC

Big advances seen in breast cancer survival

HE 10-YEAR survival rate reached 76.5% for women diagnosed with any stage breast tumour in 1995-2004, Aman U. Buzdar, MD, and colleagues at MD Anderson Cancer Center in Houston discovered when looking back at outcomes at their institution. This rate marked a steady rise from just 25.1% in 1944-1954 (P<0.0001 for trend), they reported at the American Society of Clinical Oncology's Breast Cancer Symposium. Dramatic improvements were also seen across the various stages of cancer, which the group attributed to advances in early detection and combined modality treatment. "This study shows us how our care of patients has evolved at a rapid pace," commented Jennifer Obel, MD, an ASCO Communications Committee member. "I think we can hope that the next decade will show similar gains." The retrospective review included all 12,809

(P<0.0001 for trend). "This is a dramatic shift because of the combined modality approach often utilising systemic therapy before or after surgery," Buzdar told reporters. "A dramatic shift in natural history is evident." Even for those who presented with cancer disseminated to distant sites, improvements were seen "This is a dramatic shift from 3.3% alive at 10 years among because of the combined modality those seen in 1944 to 1954 up to 22.2% by 1995-2004, again a approach often utilising systemic significant trend at P<0.0001. "This therapy before or after surgery." improvement can be attributed to a number of therapeutic agents available to treat these patients," he suggested in the press conference. The findings likely generalise to other centres since similar trends from 55.0% in the first decade of the study have been seen in the Surveillance, period when radiation therapy was the Epidemiology and End Results (SEER) mainstay of treatment to 86.1% by 1995databases, Buzdar noted. And while the 2004 (P<0.0001 for trend). For regional results represented outcomes at an academic disease with skin or lymph node involvement, medical centre, the same treatments can be 10-year survival improved from a dismal offered in community hospitals, he added. 16.2% to 74.1% over the same period Obel agreed. "The approach to cancer care in the U.S. has moved to a multidisciplinary coordinated approach across the country and in community hospitals." Dramatic improvements in medication have played a role as well, she explained. "Research advances are quickly taken up in the oncology community such that advances with the use of trastuzumab in adjuvant therapy when they are presented at national meetings are quickly taken up at smaller, more regional hospitals," she said at the briefing. patients diagnosed and seen for their initial breast cancer therapy at MD Anderson between 1944 and 2004. For local disease, the number of women alive at 10 years rose

Reference: Buzdar K, et al. Improving survival of patients with breast cancer over the past 6 decades: The University of Texas M.D. Anderson Cancer Center experience. ASCO Breast 2010; Abstract 176.

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Breast cancer survivors have an ongoing risk of lymphoedema

EPENDING ON the criteria used to define lymphoedema, the five-year incidence ranged from 43% to 94%. Regardless of the definition employed, lymphoedema incidence continued to increase during months 12 to 36 and months 36 to 60, as reported at the American

"We find that there still is an occurrence of lymphoedema, after the latest treatment and based on the current protocols."

Society of Clinical Oncology's Breast Cancer Symposium. The findings defy conventional wisdom that lymphoedema persists only for the first 12 months after treatment, said Jane M. Armer, PhD, of the University of Missouri School of Nursing in Columbia. They also run counter to the belief that modern treatment techniques have substantially reduced the risk of lymphoedema. "We find that there still is an occurrence of lymphoedema, after the latest treatment and based on the current protocols," Armer said. "More cases of lymphoedema are seen between six and nine months after treatment, but even after 60 months we still see new cases, so there are late-occurring cases. Regardless of the criteria we used to define lymphoedema, the incidence continued to increase during follow-up to 60 months." As many as 40% of women with newly diagnosed breast cancer develop lymphoedema after treatment. Initially, the swelling causes

discomfort and possibly some disability. Subsequently, the condition can cause cellulitis and lymphangitis, predisposing patients to potentially life-threatening systemic infection. Reports in the medical literature have widely varying estimates of lymphoedema incidence, from 6% to more than 60%. Medical textbooks tend to have more moderate estimates in the range of 15% to 20%. The wide variation reflects the difficulty of attaining accurate measurement, diagnosis, and followup of patients, according to the poster presentation by Armer and colleagues. In an effort to resolve some of the discrepancies, investigators prospectively followed 211 patients with newly diagnosed breast cancer for 60 months. They used three methods to assess lymphoedema: perometry, circumference by tape measure, and self-reported signs and symptoms. On the basis of the three assessment techniques, Armer and colleagues used four criteria to identify lymphoedema: A 2cm change in circumference at any measured site A 200mL perometry limb volume change (LVC) in an affected arm

10% perometry LVC of the affected arm Self-reported limb swelling or heaviness Patients were assessed before and shortly after treatment and then at follow-up visits every three months for the first year and then every six months, until reaching a total followup of 60 months. By the four different criteria used to define lymphoedema, the 12-month incidence ranged from 22% to 66%. At 60 months, the range of lymphoedema incidence was higher when categorised by all four definitions: 94% when defined by a 2cm change in circumference 83% by 200mL change in LVC 55% by 10% perometry LVC of the affected arm 43% by signs and symptoms Ongoing analysis of the data includes a focus on identifying factors associated with late-occurring lymphoedema, said Armer. Reference: Armer J, et al. Lymphoedema occurrence rates 1 to 5 years after breast cancer diagnosis. ASCO Breast 2010; Abstract 180.

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European Medicines Agency

highlights

by Gary Finnegan

EMA expects stable number of new medicines

HE EUROPEAN Medicines Agency (EMA) says it expects the number of medicines approved this year to hold steady at around 97, compared to 95 in 2010. The EMA has seen its workload grow rapidly over the past decade but looks set for a more stable period as the number of new drugs tapers off. A recruitment freeze means no new staff will be appointed this year, with the exception of a new Executive Director to replace Thomas Lönngren who stepped down at the end of December. A dispute between the European Commission and the EMA over the salary for Lönngren’s replacement has left the regulator without a director until the summer. In the absence of a new executive director, the Agency’s board published a new Road Map to 2015 in which it pledges to expand the EMA’s role in public health, facilitating access to medicines, and optimising the safe use of medicines. Meanwhile, the EMA and European Centre for Disease Prevention and Control (ECDC) have agreed to step up cooperation on vaccines, antimicrobial resistance and antiviral medicines. The two EU bodies will also work more closely on the use of human tissue and cells in medicines. The two organisations have worked side by side since the outbreak of the H1N1 influenza pandemic in 2009 and will now improve their systems for sharing information.

Public consultation on clinical trials The Agency has published a reflection paper on the need for active control in therapeutic areas where use of placebo is deemed ethical and one or more established medicine is available. The reflection paper is open for public consultation until the end of March 2011. The paper outlines a framework for the discussion and justification of the choice of control arms that is expected from an applicant in a centralised marketing authorisation application. The EMA said three-arm trials including experimental medicine, placebo and active control represent a scientific gold standard but there are situations where such trials are not required by the Committee for Medical Products for Human Use (CHMP).

Stakeholders are invited to feed into the EMA’s policy on this subject by submitting responses before 31 March.

Avastin review concluded The CHMP’s review of the risks and benefits of Avastin (bevacizumab), from Roche Registration Ltd, has confirmed that the benefits of Avastin in combination with paclitaxel outweigh its risks and that this combination remains a valuable treatment option for patients suffering from metastatic breast cancer. The CHMP also concluded by majority that Avastin in combination with docetaxel should no longer be used in the treatment of metastatic breast cancer. Patients who are currently being treated with this combination should discuss their ongoing treatment with their doctor, the EMA said in a statement. Avastin is an anticancer medicine which contains the active substance bevacizumab. It is used in combination with other anticancer treatments to treat cancers of the colon, rectum, lung, kidney or breast. The CHMP’s review was restricted to the use of Avastin in breast cancer and does not affect its use in the other indications.

New medicinal products The Committee adopted four positive opinions by consensus and one by majority (Xeplion) recommending the granting of marketing authorisations for the following new medicines: Esbriet (pirfenidone), an orphan medicine from InterMune Europe Ltd, intended for the treatment of idiopathic pulmonary fibrosis; Orphacol (cholic acid), an orphan medicine from Laboratories CTRS, intended for the treatment of inborn errors in primary bile acid synthesis; Teysuno (tegafur/gimeracil/oteracil), an orphan medicine from Taiho Pharma Europe Ltd, intended for the treatment of advanced gastric cancer in adults when given in combination with cisplatin; Xeplion (paliperidone) from Janssen-Cilag International N.V., for the treatment of schizophrenia; Xiapex (collagenase clostridium histolyticum), from Pfizer Ltd, intended for the treatment of Dupuytren’s contracture in adult patients with a palpable cord.

The Committee also adopted positive opinions by consensus recommending the granting of marketing authorisations for the informed consent applications Daliresp and Libertek (roflumilast), from Nycomed GmbH, intended for the maintenance treatment of severe chronic obstructive pulmonary disease associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment. The CHMP also adopted a positive opinion on fingolimod 0.5mg (Gilenya) from Novartis. The new daily pill is a disease modifying therapy in patients with highly active relapsing-remitting multiple sclerosis (RRMS) despite treatment with beta interferon, or in patients with rapidly evolving severe relapsing-remitting MS. The decision makes fingolimod the first daily MS pill to be recommended for approval in the European Union and follows the approval of fingolimod in Russia and the United States. Until now, many people with MS have had to self inject at least weekly or travel to hospital for infusions. Generic medicinal products The Committee adopted three positive opinions by consensus recommending the granting of marketing authorisations for: Ifirmacombi (irbesartan hydrochloride /hydrochlorothiazide), from Krka, d.d., Novo mesto, intended for the treatment of adult patients with essential hypertension, whose blood pressure is not adequately controlled with irbesartan or hydrochlorothiazide alone. Ifirmacombi is a generic of CoAprovel; Leflunomide Teva (leflunomide), from Teva Pharma B.V., intended for the treatment of adult patients with active rheumatoid arthritis. Leflunomide Teva is a generic of Arava; Repso (leflunomide), from Teva Pharma B.V., intended for the treatment of adult patients with active rheumatoid arthritis and active psoriatic arthritis. Repso is a generic of Arava. Separately, the Committee adopted a positive opinion by consensus for an application for extension of the therapeutic indication for Simponi (golimumab), from Centocor B.V., to include adult patients with severe, active and progressive rheumatoid arthritis (RA) not previously treated with methotrexate and to include reduction in the rate of progression of joint damage in all RA populations.

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Journal reviews by Bruce Sylvester

Reporting from some of the latest articles in

www.nejm.org

Common antibiotic significantly relieves symptoms of irritable bowel syndrome

LINICAL TRIALS suggest that treatment with rifaximin provides significant relief of irritable bowel syndrome symptoms, including bloating, abdominal pain and loose or watery stools. And the benefits of treatment with rifaximin persisted for 10 weeks after treatment ended, said Yehuda Ringel, MD, an associate professor of medicine in the University of North Carolina School of Medicine in Chapel Hill, and a coauthor of the studies published recently in the New England Journal of Medicine. "These results support the idea that intestinal microbiota or gut bacteria may be an underlying cause of IBS, and altering gut bacteria by treatment with rifaximin appears to be an effective way of providing relief to those who suffer from IBS symptoms," Dr. Ringel said. Researchers conducted the two parallel studies, TARGET 1 and TARGET 2, from June 2008 through June 2009. They enrolled 1,260 patients diagnosed with irritable bowel syndrome (IBS) without constipation. They randomised the subjects to receive rifaximin 550mg, three times daily for two weeks, or placebo. All subjects were tracked for 10 weeks following treatment. The investigators reported that during the first four weeks after treatment, 40.7% of the patients in the rifaximin group achieved

adequate relief of global IBS symptoms, compared to 31.7% in the placebo group. Also, 40.2% of the rifaximin subjects achieved adequate relief of bloating, compared to 30.3% of the placebo subjects. Significantly more rifaximin subjects achieved adequate reductions of abdominal pain and loose or watery stools. The authors concluded that, for up to 10 weeks after completion of treatment, 550mg doses of rifaximin taken three times a day for 14 days provides better relief of IBS symptoms than placebo. Dr. Ringel also noted that rifaximin, a semisynthetic antibiotic, has low systemic absorption (over 99% is eliminated in the stool), good antibacterial activity, low microbial resistance and a high safety profile. "These studies support the idea that gut bacteria have an important role in maintaining normal intestinal function and emphasise the need for further research on the interaction between the intestinal microbiota and the human host," Dr. Ringel said.

www.thelancet.com

Over 600,000 deaths annually worldwide caused by passive smoking

ESEARCHERS REPORT that approximately one in 100 deaths annually is caused by passive smoking, or more than 600,000 deaths each year. Approximately 165,000 of these deaths are among children. Dr. Annette Prüss-Ustün of the World Health Organisation (WHO) in Geneva, Switzerland, and colleagues reported these findings in an article published online in The Lancet recently. The study is the first effort to evaluate the global impact of second-hand smoke. For consistency of comparison, the investigators evaluated data from 2004, the last year to include comprehensive data across 192 countries. They estimated deaths and lost years of good health (DALYs). They found that 40% of children, 33% of male non-smokers and 35% of female nonsmokers were exposed to second-hand smoke in 2004. This exposure was estimated to have caused 379,000 deaths from ischaemic heart disease, 165,000 from lower respiratory infections, 36,900 from asthma and 21,400 from lung cancer.

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They also found that 603,000 deaths were attributable to second-hand smoke in 2004, which was about 1% of worldwide mortality. They noted that 47% of deaths from secondhand smoke occurred in women, 28% in children, and 26% in men. They found 10.9 million years of good health (DALYs) lost to second-hand smoke, about 0·7% of total worldwide burden of diseases in DALYs in 2004. Also, 61% of DALYs were in children. The largest disease burdens were from lower respiratory infections in children younger than 5 years (5,939,000/54%), ischaemic heart disease in adults (2,836,000/26%), and asthma in adults (1,246,000/11%) and children (651,000/6%). Deaths due to passive smoking in children were higher in low-income and middle-income countries, but deaths in adults were spread evenly across countries of all income. In the high-income countries of Europe, only 71 child deaths occurred, while 35,388 deaths occurred in adults. In Africa, among those countries assessed, an estimated 43,375 children died due to passive smoking compared with 9,514 adults. The authors wrote, “Two-thirds of these deaths occur in Africa and south Asia. Children’s exposure to second-hand smoke most likely happens at home. The combination of infectious diseases and tobacco seems to be a deadly combination for children in these regions and might hamper the efforts to reduce the mortality rate for those aged younger than five years as sought by Millennium Development Goal 4. Policy makers should bear in mind that enforcing complete smoke-free laws will probably substantially reduce the number of deaths attributable to exposure to second-hand smoke within the first year of its implementation, with accompanying reduction in costs of illness in social and health systems.” The authors conclude: “Policy makers should also take action in two other areas to protect children and adults. First, although the benefits of smoke-free laws clearly extend to homes, protection of children and women from secondhand smoke in many regions needs to include complementary educational strategies to reduce exposure to second-hand smoke at home. Voluntary smoke-free home policies reduce exposure of children and adult non-smokers to second-hand smoke, reduce smoking in adults, and seem to reduce smoking in youths. Second, exposure to second-hand smoke contributes to the death of thousands of children younger than five years in low-income countries. Prompt

attention is needed to dispel the myth that developing countries can wait to deal with tobacco-related diseases until they have dealt with infectious diseases. Together, tobacco smoke and infections lead to substantial, avoidable mortality and loss of active life-years of children.” In a linked Lancet COMMENT, Dr Heather L Wipfli and Dr. Jonathan M Samet, Department of Preventive Medicine, Keck School of Medicine of USC, USC Institute for Global Health, University of Southern California, Los Angeles, California, said, “Although the socialnorm change that comes with smoke-free laws can spill over to homes, broad initiatives are needed to motivate families to put their own policies into place to reduce exposure to second-hand smoke at home. In some countries, smoke-free homes are becoming the norm, but far from universally.” They conclude: “There can be no question that the 1.2 billion smokers in the world are exposing billions of non-smokers to secondhand smoke, a disease-causing indoor-air pollutant. Few sources of indoor-air pollution can be completely eliminated. However, smoking indoors can be eliminated - with substantial benefits, as shown by this new set of estimates.”

BMJ www.bmj.org

E. coli contamination related to long-term health issues

ASTROENTERITIS CONTRACTED by E coli contamination of drinking water increases the risk of high blood pressure, kidney problems and heart disease later in life, researchers reported online recently in the British Medical Journal. As background the authors noted that E coli O157:H7 infections cause up to 120,000 gastroenteric illnesses annually in the US alone, resulting in over 2,000 hospitalisations and 60 deaths. The long-term effects of E coli infection in adults have been largely unknown. The investigators studied the risk for hypertension, renal impairment and cardiovascular disease. The investigators used data from the Walkerton Health Study, the first study to evaluate long term health after an outbreak of gastroenteritis in May 2000 when a municipal water system became contaminated with E coli O157:H7 and Campylobacter bacteria. The investigators in the Walkerton Health Study evaluated 1,977 adult subjects annually for 8 years. The subjects were surveyed and had

an annual physical examination and laboratory assessment to track long-term health. Of the 1,977 adult participants, 1,067 (54%) reported acute gastroenteritis during the May 2000 outbreak, and 378 sought medical attention. The investigators in this new analysis of the data found that, compared with participants who were not ill or only mildly ill during the outbreak, subjects with acute gastroenteritis were 1.3 times more likely to develop hypertension, 3.4 times more likely to develop renal impairment, and 2.1 times more likely to have a cardiovascular event, such as a heart attack or stroke during the eight years following the outbreak. "Our findings underline the need for following up individual cases of food or water poisoning by E coli O157:H7 to prevent or reduce silent progressive vascular injury," said investigator Dr. William Clark, Professor of Nephrology at Western's Schulich School of Medicine & Dentistry, University of Western Ontario in London, Ontario, Canada. "These long-term consequences emphasise the importance of ensuring safe food and water supply as a cornerstone of public health."

www.jama.ama-assn.org

Maintaining long-term, high levels of moderate and vigorous activity lowers weight gain at middle age

DULTS WITH high levels of moderate and vigorous activity during 20 years prior to middle-age show smaller gains in weight and waist circumference during the transition from young adulthood to middle age, compared to adults with lower activity, researchers reported in a recent issue of JAMA. As background, the authors noted that the prevalence of obesity has increased markedly since 1976, now exceeding 30% among U.S. adults. While studies have examined treatments for obesity, there is little data supporting physical activity guidelines to prevent long-term weight, especially during the high-risk transition to middle age. Arlene L. Hankinson, M.D., M.S., of the Feinberg School of Medicine, Northwestern University, Chicago, and colleagues evaluated the relationship between maintaining higher activity levels and changes in body mass index (BMI) and waist circumference over 20 years in

young adults. The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective study with 20 years of follow-up, 1985-1986 to 2005-2006. The investigators defined habitual activity as maintaining high, moderate, and low activity levels based on sex-specific groupings of activity scores at the beginning of the study. The study included 3,554 men and women, ages 18 to 30 years at baseline. At follow-up, subjects completed annual questionnaires, which asked about 13 specific moderate- and vigorous-intensity activities over the previous year, including sports, exercise, home maintenance, and occupational activities. The investigators reported that, over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels, after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use and energy intake. They wrote, “Men maintaining high activity gained 2.6 fewer kilograms [5.7lbs.] per year (+0.15 BMI units vs. +0.20 in the lower activity group), and women maintaining higher activity gained 6.1 fewer kilograms [13.4lbs.] per year (+0.17 BMI units vs. +0.30 in the lower activity group). Men maintaining high activity gained 3.1 fewer centimeters [1.2 inches] in waist circumference per year (+0.52cm vs. 0.67cm in the lower activity group) and women maintaining higher activity gained 3.8 fewer centimeters [1.5 inches] per year (+0.49cm vs. 0.67cm in the lower activity group).” Weight gains in participants with moderate or inconsistent activity levels were not generally different from the low-activity group. “Importantly, women seemed to benefit the most from maintaining higher activity; the magnitude of weight change was more than twice as large among women compared with men. Similarly, participants who maintained the Health and Human Services-recommended 150 minutes of moderate activity per week gained significantly less weight compared with participants who did not.” “These results suggest that maintaining higher activity levels during young adulthood may lessen weight gain as young adults transition to middle age,” the researchers said. “Our results reinforce the role of physical activity in minimising weight gain and highlight the value of incorporating and maintaining at least 30 minutes of activity into daily life throughout young adulthood.”

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Medical news from around the world by Gary Finnegan

World Health Matters FRANCE French women light up as men kick habit THE PAST two decades have seen a marked reduction in the number of male smokers in France, but their female counterparts show no signs of following the trend. This pattern may significantly influence mortality rates from coronary heart disease, say experts. The prevalence of smoking and exposure to tobacco smoke among men in France has fallen by more than 15% since the mid 1980s, but over the same 20-year period has increased among women. Investigators from the World Health Organisation French MONICA (MONItoring trends and determinants in CArdiovascular disease) centre say the divergent smoking trends are striking. “The prevalence of smoking in men has been high for the past 60 years and is now tending to fall, whereas women only started to smoke in large numbers much more recently,” say researchers. Evidence is presented in the latest report of the MONICA investigators published in the European Journal of Cardiovascular Prevention and Rehabilitation. The results are based on detailed surveys of mid-life adults (aged 35-64 years) in three distinct geographical regions of France: the Lille urban community in the north; the Bas-Rhin department in the east; and the Haute-Garonne department in the south. The surveys were conducted at three time points 1985-87, 1995-97 and 2005-07, and involved a total of more than 10,000 subjects. They were each asked about earlier or current tobacco consumption, the number of cigarettes smoked per day, age at first cigarette, pipe tobacco and cigar consumption, quit attempts, age at quitting, and secondhand exposure. Answers provided not just a snapshot of smoking trends in France, but also a database by which the contribution of tobacco exposure to heart disease mortality risk could be plotted. The study found the age when men smoke their first cigarette has remained stable at approximately 17.5 years. However women now begin smoking at 18.8 years compared to 21.4 years in the mid 1990s. The number of

men who never smoke has increased from 25% to 38% whereas the number of women who never smoke has fallen from 72% to 55%. When these figures were introduced to a risk prediction model, the estimated cardiovascular mortality rate was approximately 10% lower in men aged 35-54 years and 15% lower in men aged 55-64 years. However, in women the predicted heart disease mortality rate was higher by up to 4.9% between 1995-97 and 2005-07. Commenting on the results of the study investigator Dr. Jean Dallongeville from the INSERM Institut Pasteur in Lille, France, said anti-tobacco initiatives much be continued to curb the increase in female smokers and build on the successes seen in cutting the number of male smokers.

UNITED STATES Foreign-born children ‘less likely to have asthma’ THE LIKELIHOOD of developing childhood asthma may be linked to country of birth, according to a new study. Researchers at Tufts University looked at data on asthma prevalence in children living in poor neighbourhoods in Boston and compared results for those born in the United States and those whose families moved to the U.S. when they were children. Among children born in the U.S., low socioeconomic status (SES) and exposure to pests (mice and cockroaches) were both associated with having asthma. Neither association was present in children born outside of the U.S. The study, published in the Journal of Immigrant and Minority Health, appears to lend weight to the so-called “hygiene hypothesis” which suggests that children born in lessdeveloped countries may have early exposure to intestinal worms, viruses and bacteria that affects immunity and makes them more resistant to asthma than American-born children. However, the exact mechanism behind such a theory requires further study. Dr. Doug Brugge, senior author and professor of public health and community medicine at Tufts University School of Medicine, said the findings highlight the importance of

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studying foreign-born children and could bring a new perspective to asthma research. “Much of the existing research follows U.S.born children from birth to see if, and potentially why, they develop asthma. [This study] might add to our understanding of what causes asthma if we knew why foreign-born children seem to be less likely to develop asthma,” he said. Dr. Mark Woodin, lead author of the report, said the research was based on a large sample size using pooled data from several previous studies. However, he cautioned against jumping to conclusions based on correlations observed in the report. “While this type of epidemiological study cannot establish causation, our findings may be explained by the fact that certain pathogens common in the developing world are nearly nonexistent in the U.S. If exposure to such pathogens confers some sort of protection against developing asthma, foreign-born children may be less susceptible than children born in the U.S.,” Brugge added. In addition to the hygiene hypothesis, there are other ideas on why American children have higher asthma rates than those who move to the U.S. later in life. “The vitamin D hypothesis posits that greater sunlight exposure in the country of origin increases vitamin D to levels that are protective against asthma. It could also be that families who emmigrate tend to be healthier people," speculated Brugge. Reference: Woodin M, Tin AH, Moy S, Palella M and Brugge D. Journal of Immigrant and Minority Health "Lessons for Primary Prevention of Asthma: Foreign-Born Children Have Less Association of SES and Pests with Asthma Diagnosis." Published online, October 16, 2010

ISRAEL Half of children with flu complications had underlying illness ALMOST 50% of children who were hospitalised following severe complications caused by the A/H1N1 influenza virus during

the 2009 pandemic had underlying conditions, according to new research. A study by Dr. Michal Stein and colleagues of Edith Wolfson Medical Centre, Holon, Israel, found that these illnesses may have predisposed children to complications after infection with the novel flu strain. The team assessed data from children hospitalised with the A/H1N1 influenza virus which caused the WHO to declare a flu pandemic for the first time in 40 years. Studying admissions at seven medical centres in Israel between July 12, 2009, and December 24, 2009, researchers said the severity and mortality rates were lower than had previously been reported. “Our study showed that the severity and mortality of 2009 influenza A(H1N1) in Israel were milder than those described in earlier publications and were similar to the figures reported in the literature on seasonal influenza,” the authors wrote. “Children with underlying metabolic and neurologic disorders represent the group at highest risk for severe complications following 2009 influenza A(H1N1) infection. Our results also suggest that children with cyanotic heart lesions and infants born prematurely are two additional populations at significant risk for a complicated hospital course following infection with 2009 influenza A(H1N1) virus,” the report says. The most frequent clinical presentations were pneumonia, influenza-like illness, wheezing exacerbation and convulsions, according to the report. Of the 478 patients studied, the average age was 6.1 years. About 9% (42 patients) were admitted to the paediatric intensive care unit and 0.6% (three patients) died. Underlying illnesses that predisposed children to complications were detected in 48.7% of patients. By comparison, a U.S. report published in the same journal - Archives of Pediatrics & Adolescent Medicine - found that more than one quarter of children hospitalised with 2009 novel influenza A(H1N1) in California required intensive care or died. Two-thirds of those who died or were hospitalised had co-occurring illnesses. More than half had pneumonia, 27% required intensive care and 3% died. In addition, more than two-thirds of the children received antiviral

treatment, including 44% who were treated within 48 hours of developing symptoms. The most common symptoms included fever, cough, shortness of breath or difficulty breathing, nausea or vomiting, diarrhoea and muscle aches. Factors associated with an increased risk of death or admission to the intensive care unit included congenital heart disease and cerebral palsy or developmental delay; Hispanic children were less likely than white children to experience either outcome. Reference: Arch Pediatr Adolesc Med. 2010; 164[11]: 1023-1031, 1015-1022.

SPAIN Synthetic iron compounds could stifle TB A TEAM of researchers from Spain and South America have synthesised two iron compounds that inhibit the in vitro growth of Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Due to their low level of toxicity in mammal cells, the compounds could be used in the future as therapeutic agents and hospital disinfectants, say scientists. A group from the Universidad de Navarra in Spain, the Universidad de la República in Uruguay, the Universidad de São Paulo in Brazil, and the Universidad Nacional de La Plata in Argentina have synthesised two iron complexes “that showed in vitro growth inhibitory activity on Mycobacterium tuberculosis.” Dinorah Gambino and María Torre, authors of the study published in the Journal of Inorganic Biochemistry said the team used iron atoms to join organic molecules (derived from quinoxaline), forming compounds that act as

bactericides or bacteriostatic agents which prevent bacteria from reproducing. The organic molecules were synthesised at the Universidad de Navarra. “One of the greatest problems in relation to the pharmacotherapy for treating tuberculosis is the appearance of bacteria resistant to current medicines, which is why it is important to develop new active ingredients,” the researchers said. Treating tuberculosis typically begins with “first-line” antibiotics such as isoniacide or estreptomicine, but when side effects appear, or in cases of stronger resistance, doctors resort to “second-line” antibiotics such as cicloserine or ciprofloxacin. The new compounds inhibit M. tuberculosis better than the “second-line” medicines. Another advantage of the iron compounds is that they show low toxicity in mammal cells, as demonstrated by the experiments performed with mice cells. “That is why these compounds are useful as hospital disinfectants or therapeutic agents and the line of research remains open to learn more about how they act,” said the researchers, noting that the work to date is based on in vitro trials. Antonio Monge, co-author of the study and a researcher at the Universidad de Navarra, Spain, underlined the importance of cooperating with research centres in Latin America, where there are many cases of tuberculosis and other diseases such as malaria or Chagas disease. Tuberculosis kills more than one million people a year worldwide. At present, tuberculosis is considered a re-emerging disease due to the increase in the number of people with HIV and other viruses that attack the immune system, as well as to the increasing consumption of immunosuppressive and recreational drugs. The World Health Organisation (WHO) estimates that 30 million people will be infected by tuberculosis over the next 20 years. Reference: Tarallo M.B., Urquiola C., Monge A., Costa B.P., Ribeiro R.R., Costa-Filho A.J., Mercader R.C., Pavan F.R., Leite C.Q., Torre M.H. y Gambino D. "Design of novel iron compounds as potential therapeutic agents against tuberculosis.” Journal of Inorganic Biochemistry 104 (11): 1164-1170, noviembre de 2010.

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FDA highlights by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs Combo treatment prevents HIV transmission in HIV-negative men who have sex with men

ESEARCHERS REPORT an estimated 43.8% reduction of new HIV infections among men who took an antiretroviral tablet daily to prevent HIV, compared with those who took a placebo. Results of the world's first efficacy trial (iPrEx Trial) of an HIV-prevention approach called oral pre-exposure prophylaxis (PrEP) appeared recently in the New England Journal of Medicine.

While this level of efficacy is relatively strong, PrEP is not quite ready for prime time and work remains before this strategy is rolled out. However, we are thrilled to have a new prevention option beyond male and female condoms visible on the horizon.

"This discovery alters the HIV prevention landscape forever," said Jim Pickett, AIDS Foundation of Chicago, and International Rectal Microbicide Advocates, Chicago, Illinois. "While this level of efficacy is relatively strong, PrEP is not quite ready for prime time and work remains before this strategy is rolled out. However, we are thrilled to have a new prevention option beyond male and female condoms visible on the horizon." The investigators evaluated the safety and efficacy of the antiretroviral (ARV) drug emtricitabine and tenofovir disoproxil fumarate (TDF/FTC; brand name, Truvada) taken once daily for HIV prevention among HIV-negative homosexual men, transgender women, and other men who have sex with

men (MSM). There were 2,499 subjects from Peru, Ecuador, Brazil, South Africa, Thailand, and the United States. The researchers randomised half the men to TDF/FTC and the other half to placebo. The study was double-blinded. Enrolment began in June 2007 and ended in December 2009. Primary analysis of the results included subjects followed until May 1, 2010, with an average of 14 months. Subjects were tested for HIV at monthly trial visits and given intensive pre-and-post test counseling. They were regularly screened for sexually transmitted infections and received condoms. The investigators reported 36 infections among TDF/FTC subjects and 64 among placebo subjects. The use of TDF/FTC reduced new HIV infections by an estimated 43.8% overall when compared with placebo. There were few side effects reported by the men taking the combination ARV tablet. The researchers emphasised that efficacy appeared to be higher among subjects who took the study drugs consistently. Subjects who failed to take the treatment regularly did not have a protective benefit. "The study team found that about half of the men in the active arm of the trial were in fact not taking their pills regularly, if at all," said Pickett. "It is not clear why this happened, but it certainly suggests that alternate means of using ARVs to prevent HIV infection may be more acceptable for these men. The primary means of transmission among gay men and other MSM is through unprotected anal intercourse. If we develop an ARV as a gel or lubricant applied rectally - a rectal microbicide - it could be more acceptable for some individuals who don't like taking pills."

Teriparatide heals bone in patients with gum disease

REATMENT WITH teriparatide heals bone wounds in patients with periodontal disease, researchers reported in the recent issue of the New England

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Journal of Medicine. They also presented their findings recently at the American Society of Bone and Mineral Research (ASBMR) 2010 Annual Meeting. "This new approach for the treatment of periodontal disease could allow us to rebuild some of the bone that is lost due to periodontal disease, which until this point has been very difficult to achieve," said Jill Bashutski, MD, University of Michigan School of Dentistry, Ann Arbor, Michigan. "Current treatments to regrow bone around teeth affected with gum disease have limited success rates." Periodontal gum disease is the leading cause of tooth loss in adults; it is also associated with other health problems. Subjects with severe chronic gum disease received the traditional treatment, periodontal surgery on one-quarter of the mouth. Half of the patients received a 6-week course of injected teriparatide (into the skin over the abdomen or stomach), plus calcium and vitamin D supplements. The other half received placebo injections. After one year, researchers reported a 29% improvement in bone-level measurements on x-rays in the teriparatide group compared to a 3% improvement in the placebo group. "I think one really interesting aspect of this study is that even a short dosing of this drug had benefits that lasted one year," said Laurie McCauley, DDS, PhD, University of Michigan School of Dentistry. Dr. McCauley also said that researchers must now test whether the treatment can be delivered locally, in order to target site-specific periodontal disease.

Celecoxib could prevent nonmelanomaskin cancer

REATMENT WITH celecoxib appears to help prevent non-melanoma skin cancers in patients with extensive actinic keratosis, researchers reported in the recent issue of The Journal of the National Cancer Institute. As background, the authors noted that

non-melanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), are among the most common cancers in the United States, and actinic keratosis can be a precursor to these cancers. The incidence of these malignancies is rising, notably in young adults. UV-protective sunscreens have not been highly effective in reducing the incidence of these cancers, so researchers have begun seeking other forms of prophylaxis. Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), inhibits the enzyme cyclooxygenase 2, which is widely believed to be involved in the development of UV-induced non-melanoma skin cancers. Craig Elmets, MD, University of Alabama at Birmingham, Alabama, and colleagues conducted a double-blind, placebocontrolled, randomised trial enrolling 240 subjects who had been diagnosed with actinic keratoses. They examined each subject for new lesions after 3, 6, and 9 months of celecoxib or placebo treatment, and at 2 months following the completion of therapy. At enrolment, the number of new precancerous lesions in the two groups was the same. By the end of the trial, the investigators found that the group taking celecoxib had

significantly fewer total non-melanoma skin cancers compared with those taking a placebo. The researchers write, "The findings of this study, which showed that the celecoxibtreated individuals developed fewer non-

The incidence of these malignancies is rising, notably in young adults. UV-protective sunscreens have not been highly effective in reducing the incidence of these cancers, so researchers have begun seeking other forms of prophylaxis.

melanoma skin cancers than placebo-treated individuals, suggest that cyclooxygenase inhibitors may provide an additional benefit to sunscreens in the prevention of nonmelanoma skin cancers." The finding that celecoxib did not reduce the number of precancerous lesions was inconsistent with animal studies showing that celecoxib reduced both precancerous lesions

and non-melanoma skin cancers. The efficacy of celecoxib against later stages of tumour development was consistent with other trials of celecoxib for colorectal adenoma. The FDA terminated the colorectal adenoma study early after preliminary findings from a concurrent trial of another cyclooxygenase 2 inhibitor showed an increased risk of cardiovascular adverse events. The investigators noted that the finding that no adverse cardiovascular events appeared with this trial could be attributed to the fact that subjects were only taking celecoxib for nine months. In an accompanying editorial, Frank L. Meyskens Jr, MD, and Christine E. McLaren, PhD, both of the University of California, Irvine, California, said that the fact that celecoxib was effective in reducing the number of nonmelanoma skin cancers, but not the number of precancerous lesions, suggests that pathways of carcinogenesis might differ between early- and late-stage tumour development. Sources: University of Michigan, International Rectal Microbicide Advocates, The Journal of the National Cancer Institute.

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View from the waiting room by Steve Devrell

E ‘sick’BAY A

LTHOUGH MY articles come under the heading View from the Waiting Room, I don’t really know what my waiting room looks like, let alone the view. Fortunately, I have only visited my doctor a couple of times in the last five years and one of those was for athlete’s foot! What I have become a bit of an expert on over that time however is looking up symptoms on the internet. Call me one of the ‘worried well’ if you like or just a bit of a hypochondriac, but the internet has become a great comfort to me over the years as I indulge in the hazardous practice of self-diagnosis. I am clearly not alone. If one ‘Googles’ the word heartburn, there are over 14 million sites to choose from , 11 million for the common cold, 6.5 million for Influenza, 4 million for chlamydia and a quarter of million for poor old haemorrhoids.

The Department of Health claim that more patients than ever are going online to find health information and self-diagnosis and in so doing they are saving the NHS millions of pounds each year.

The Department of Health claim that more patients than ever are going online to find health information and selfdiagnosis and in so doing they are saving the NHS millions of pounds each year. Over 100 million people visited the NHS Choices website last year, up 10% on the 2009 figures. A separate report from Imperial College found a third of those logging on to the NHS website avoided booking an appointment with their GP, because they were able to find the information they were looking for. This action resulted in a potential saving for the NHS of £44 million a year. In a recent Which? investigation into medical websites, the NHS Choices website was found to be excellent for its breadth of coverage and it contained ‘medically robust information’. In addition, over 40,000 patients posted comments about hospitals and GP practices. Perhaps a downside of this kind of interaction is that the internet is rarely a medium for the contented! The British Medical Journal recently sounded a note of caution about the overuse of the internet in providing

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health related advice. Although admitting the net does have its place, the patient must be aware of the variation in quality that the internet gives and the healthcare professional should always be the main source of information for patients. The BBC in April 2010 also warns patients against overuse of the internet as an organ for self-diagnosis. Basing their report on a wide range of current research, the BBC conclude that “typing in your medical problems is unlikely to deliver much in the way of good advice.” A team of researchers from the University of Nottingham, used the ‘net’ to discover UK based advice on five common issues relating to child health. These issues included breastfeeding and autism. Their research found that only 200 of 500 sites offered correct information and the government-run sites were the only completely reliable source. Another study by the Nottingham NHS Trust looked at advice for children with a fever. They found that only 3 out of 22 sites visited gave information that matched current ‘best practice guidelines’. The research also found that ‘sponsored links’ appeared prominently, even though the information they contained was not closely related to the search terms. But once again, the governmental websites such as NHS Direct and NHS Choices were found to be accurate and researchers suggested that they should be recommended more widely by doctors and health professionals. An earlier study by the BBC, based on research carried out by University College London warned that people with chronic diseases should think twice before relying on the internet for health advice. The study conceded that the internet did have a positive effect on improving people’s medical knowledge, but there was no evidence to suggest that it changed people’s behaviour positively. The UCL team reviewed the effect of the internet on people with long-term conditions such as diabetes and asthma. In total they looked at 28 studies covering 4,042 participants. Lead researcher Dr. Elizabeth Murray said that she found the ‘net’ did boost the medical knowledge of patients, but, if anything, had a negative effect on the user’s health. Dr. Murray said one reason for the apparent paradox may be that titbits of information may lull users into a false sense of security. Thus they become less motivated to control their condition in the way they would if faced with a blunt instruction from a doctor. The study also suggested that other assumptions about interactive health care were flawed. Further, it may well be that the ‘internet-savvy’ health consumer may not, as expected, drive down the use of health care, but may

increase it by demanding specific and possibly more costly treatments. The research concluded that more work needed to be done to fully understand the negative effect of interactive health applications on clinical outcomes.

The problem is how do you know if this information and advice is reliable and worth heeding? Separating fact from fiction is a concern, but most of us are aware of the net’s shortfalls.

Arguably, the area where the internet has had the biggest impact in health information is in patient forums. Vivienne Parry, writing in The Times suggests that health information on the internet that used to be shaped by doctors is now being shaped by patients. They are providing the information that patients really want to know. The problem is how do you know if this information and advice is reliable and worth heeding? Separating fact from fiction is a concern, but most of us are aware of the net’s shortfalls. It is easy to detect blatant commercial agendas that present opinion as fact and it is also easy to weed out the downright bonkers! What the internet does provide is immediacy and confidentiality. Dr. Murray from UCL states that doctors can deliver the clinical details of a condition, but they sometimes struggle to understand the emotional and social implications. This is where patient websites come into play and she believes they perform a vital role. Research does show that people like to know what their illness has meant to other sufferers. She adds that patient-led sites can deliver information that may be hard to find elsewhere. “If someone wanted to

know which travel insurers cover people with diabetes, the best place to get this information is from other patients.” There are also examples where patient-led sites have become vital to many people. Mental health sites for instance are used by more than 10,000 people each year and have become a critical tool in helping to live a normal life. Another successful patient-led site is www.downyourdrink.org.uk. This is a site for drinkers who are not physically dependent on alcohol, but along with 8 million others in this country, regularly drink too much. A survey of 10,000 of its users revealed that they were on average 38 years of age; half had university degrees and most had good jobs. The stark truth however, was that few of them would have sought NHS treatment until they had already harmed themselves (or others) through alcohol. The site is now part of a clinical trial assessing its health impact. In conclusion, it seems that the internet will continue to play an increasingly important part in supporting our health care. As a source of information, it is comprehensive, convenient and immediate. It also provides support from the numerous patient forums that have been established. There is a cautionary note however from Dr. Annabel Bentley, BUPA’s assistant medical director. She points out that, at present, there is no independent watchdog, so it can be potentially dangerous for people to trust it completely. Your most reliable option as a ‘symptom checker’, is still your own GP.

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