BMJ: British Medical Journal

16 June 2007 (Vol 334, No 7606),pp.1229-1280

Editor's choice Editor's choice: Lives lived Trish Groves BMJ 2007;334, doi:10.1136/bmj.39245.525046.47 US editor's choice: Someone to watch over me Elizabeth Loder BMJ 2007;334, doi:10.1136/bmj.39246.470764.3A Editorials Diagnosis of peripheral arterial disease of the lower limb Andrew W Bradbury, Donald J Adam BMJ 2007;334:1229-1230, doi:10.1136/bmj.39244.344664.80 Provision of primary care in different countries John L Campbell BMJ 2007;334:1230-1231, doi:10.1136/bmj.39237.534560.80 Transition of care in children with chronic disease Colin Wallis BMJ 2007;334:1231-1232, doi:10.1136/bmj.39232.425197.BE Tamiflu and neuropsychiatric disturbance in adolescents Simon R J Maxwell BMJ 2007;334:1232-1233, doi:10.1136/bmj.39240.497025.80 Rosiglitazone and implications for pharmacovigilance Dhruv Kazi BMJ 2007;334:1233-1234, doi:10.1136/bmj.39245.502546.BE Letters This week's letters Doctors and alcohol: Investing in alcohol is no longer responsible Joseph M Barry, Tom O'Dowd BMJ 2007;334:1235, doi:10.1136/bmj.39241.435278.3A Safer play in rugby: Time to address safety in the tackle Alastair P Greystoke BMJ 2007;334:1235, doi:10.1136/bmj.39241.446030.3A

PTSD in Northern Ireland: Tell us more Adarsh Shetty BMJ 2007;334:1235-1236, doi:10.1136/bmj.39241.426192.3 Skin biopsy: Watch out for digital nerves Bo Povlsen BMJ 2007;334:1236, doi:10.1136/bmj.39241.429201.3A Rosiglitazone and heart deaths: Glycaemic control is a myth Illtyd R Thomas BMJ 2007;334:1236, doi:10.1136/bmj.39234.451296.3A Helping the world's poor: Let's help doctors work in the third world Andrew L Perkins BMJ 2007;334:1236, doi:10.1136/bmj.39241.432674.3A Trials and electronic records: A frightening industry proposal Matthew L Grove BMJ 2007;334:1236, doi:10.1136/bmj.39241.431875.3A News FDA places "black box" warning on antidiabetes drugs Janice Hopkins Tanne BMJ 2007;334:1237, doi:10.1136/bmj.39244.394456.DB Russian clinical research is threatened by ban on export of samples Vasiliy Vlassov BMJ 2007;334:1237, doi:10.1136/bmj.39241.621863.DB Gates Foundation funds new institute to evaluate global health data Peter Moszynski BMJ 2007;334:1238, doi:10.1136/bmj.39244.424965.4E NHS IT system must use unique patient identifiers to achieve research potential Susan Mayor BMJ 2007;334:1238, doi:10.1136/bmj.39245.392523.DB NICE reviews its guidance against sequential use of anti-TNF drugs for arthritis Susan Mayor BMJ 2007;334:1238-1239, doi:10.1136/bmj.39245.417292.DB Community care could prevent deaths of thousands of severely malnourished children John Zarocostas BMJ 2007;334:1239, doi:10.1136/bmj.39244.445856.4E Women treated for early breast cancer should be followed for at least 10 years Susan Mayor BMJ 2007;334:1240, doi:10.1136/bmj.39244.725810.DB Strike cripples health services in South Africa Pat Sidley BMJ 2007;334:1240-1241, doi:10.1136/bmj.39245.485579.DB

Mortality from 12 top causes of death in US is still higher among men than women Roger Dobson BMJ 2007;334:1240, doi:10.1136/bmj.39241.704757.DB US parents take government to court over MMR vaccine Clare Dyer BMJ 2007;334:1241, doi:10.1136/bmj.39244.362778.DB In Brief: News

BMJ 2007;334:1242, doi:10.1136/bmj.39244.628981.DB Congressional hearings highlight mistakes in case of tuberculosis patient Janice Hopkins Tanne BMJ 2007;334:1242, doi:10.1136/bmj.39244.374757.DB NHS ends the financial year £500m in surplus Michael Day BMJ 2007;334:1242-1243, doi:10.1136/bmj.39241.608692.DB New regulations aim to prevent international health emergencies Peter Moszynski BMJ 2007;334:1243, doi:10.1136/bmj.39241.666829.DB Government claims that it is consigning waiting lists to history Michael Day BMJ 2007;334:1243, doi:10.1136/bmj.39241.674595.DB Researchers warn of possible risks to children from new epilepsy drugs Lynn Eaton BMJ 2007;334:1243, doi:10.1136/bmj.39245.699537.DB Bush says he will veto stem cell funding, despite vote in favour in Congress Jeanne Lenzer BMJ 2007;334:1243, doi:10.1136/bmj.39245.359306.DB Shortcuts from other journals: Exercise and physiotherapy advice help subacute low back pain only in the short term

BMJ 2007;334:1244, doi:10.1136/bmj.39244.448356.801 Shortcuts from other journals: The evidence on gene mutations in hereditary diffuse gastric cancer is accumulating

BMJ 2007;334:1244, doi:10.1136/bmj.334.7606.1244-a Shortcuts from other journals: Lowering homocysteine doesn't reduce the risk of thromboembolism

BMJ 2007;334:1244-1245, doi:10.1136/bmj.334.7606.1244-b

Shortcuts from other journals: Preoperative chemotherapy improves outcomes in non-small cell lung cancer

BMJ 2007;334:1245, doi:10.1136/bmj.334.7606.1245 Shortcuts from other journals: Eprodisate slows kidney decline in amyloid A amyloidosis

BMJ 2007;334:1245, doi:10.1136/bmj.334.7606.1245-a Shortcuts from other journals: Anti-CCP antibodies are better than rheumatoid factor for diagnosing rheumatoid arthritis

BMJ 2007;334:1245, doi:10.1136/bmj.334.7606.1245-b Feature European degrees: The course left out in the cold Toby Reynolds BMJ 2007;334:1246-1248, doi:10.1136/bmj.39237.543889.AD Head to head: Should folic acid fortification be mandatory? Yes Nicholas J Wald, Godfrey P Oakley BMJ 2007;334:1252, doi:10.1136/bmj.39232.493252.47 Head to head: Should folic acid fortification be mandatory? No Richard A Hubner, Richard D Houlston, Kenneth R Muir BMJ 2007;334:1253, doi:10.1136/bmj.39232.496227.47 Observations Media watch: Why don't journalists mention the data? Ben Goldacre BMJ 2007;334:1249, doi:10.1136/bmj.39245.510718.59 Medicine and the media: Don't blame it all on the bogey Michael Day BMJ 2007;334:1250-1251, doi:10.1136/bmj.39244.680880.59 What's on the web: What's so precious about originality Simon Chapman BMJ 2007;334:1251, doi:10.1136/bmj.39245.425880.59 Analysis How effective are expert patient (lay led) education programmes for chronic disease? Chris Griffiths, Gill Foster, Jean Ramsay, Sandra Eldridge, Stephanie Taylor BMJ 2007;334:1254-1256, doi:10.1136/bmj.39227.698785.47 Research Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: systematic review Ros Collins, Jane Burch, Gillian Cranny, Raquel Aguiar-Ibáñez, Dawn Craig, Kath Wright, Elizabeth Berry, Michael Gough, Jos Kleijnen, Marie Westwood BMJ 2007;334:1257, doi:10.1136/bmj.39217.473275.55 (published 4 June 2007) Diagnostic scope of and exposure to primary care physicians in Australia, New Zealand, and the United States: cross sectional analysis of results from three national surveys Andrew B Bindman, Christopher B Forrest, Helena Britt, Peter Crampton, Azeem Majeed BMJ 2007;334:1261, doi:10.1136/bmj.39203.658970.55 (published 15 May 2007) Clinical review Acute coronary syndromes without ST segment elevation Ron J G Peters, Shamir Mehta, Salim Yusuf BMJ 2007;334:1265-1269, doi:10.1136/bmj.39220.618646.AE Practice A patient's journey: Cystic fibrosis Emma Wicks BMJ 2007;334:1270-1271, doi:10.1136/bmj.39188.741944.47 Change page: Established corticosteroid creams should be applied only once daily in patients with atopic eczema Hywel C Williams BMJ 2007;334:1272, doi:10.1136/bmj.39195.636319.80 10-minute consultation: Chronic kidney disease Prabir Kumar Mitra, Peter R W Tasker, M S Ell BMJ 2007;334:1273, doi:10.1136/bmj.39196.714491.94 Views & reviews Personal views: Communication—the forgotten palliative care emergency Mark Pickering, Rob George BMJ 2007;334:1274, doi:10.1136/bmj.39157.685220.47 Review of the week: Fractured: picking up the pieces Jessica Watson BMJ 2007;334:1275, doi:10.1136/bmj.39239.704248.4E From the frontline: 110% Des Spence BMJ 2007;334:1276, doi:10.1136/bmj.39244.556389.47 Past caring: Jobs for the boys Wendy Moore BMJ 2007;334:1276, doi:10.1136/bmj.39244.478970.59 Between the lines: The casualties of Waugh Theodore Dalrymple BMJ 2007;334:1277, doi:10.1136/bmj.39239.466516.59 Medical classics: Extensile exposure Craig Gerrand BMJ 2007;334:1277, doi:10.1136/bmj.39244.530706.59 Obituaries This week's obituaries Miles Weatherall Estlin Waters BMJ 2007;334:1278, doi:10.1136/bmj.39241.578160.BE

Josephine Alice Coreen Weatherall (née Ogston) Miranda Mugford, Alison Macfarlane BMJ 2007;334:1278, doi:10.1136/bmj.39241.530116.BE Khalid Tariq Al Naib Saad Shakir BMJ 2007;334:1279, doi:10.1136/bmj.39234.632002.BE William Bingham J S Bingham, E A Barnett BMJ 2007;334:1279, doi:10.1136/bmj.39237.689549.BE Stuart Gordon Adam Forsyth John Ford BMJ 2007;334:1279, doi:10.1136/bmj.39232.832940.BE Robert John Jameson Paul Booth, Angela Jameson, David Jameson BMJ 2007;334:1279, doi:10.1136/bmj.39234.678438.BE Geoffrey Laurence Scott Helena Daly, John Hudson BMJ 2007;334:1279, doi:10.1136/bmj.39232.788634.BE Anthony Robert ("Bob") Teuten Richard Teuten BMJ 2007;334:1279, doi:10.1136/bmj.39218.605984.BE Minerva Minerva

BMJ 2007;334:1280, doi:10.1136/bmj.39241.502789.BE1 Minerva Alexander Harris, Gordon Buchanan BMJ 2007;334:1280, doi:10.1136/bmj.39241.502789.B Fillers An event that changed our lives Geoffrey Marsh, Patrick Sweeny BMJ 2007;334:1264, doi:10.1136/bmj.39196.561030.BE Corrections Is presumed consent the answer to organ shortages?

BMJ 2007;334, doi:10.1136/bmj.39245.495590.BE Career focus Read this week's articles on

For the full versions of these articles and the references see bmj.com EDITORIALS

Diagnosis of peripheral arterial disease of the lower limb Duplex ultrasound is safe, inexpensive, and accurate enough to guide management in most cases

In this week’s BMJ a systematic review by Collins and use of limited resources. But, as Collins and colleagues colleagues compares the diagnostic accuracy of duplex report, making such a choice can be difficult in people ultrasound, magnetic resonance angiography, and com� with peripheral arterial disease. They could find few puted tomography angiography for assessing periph� comparative studies and many had serious methodo� eral arterial disease of the lower limb.1 The review also logical limitations. Most studies had several potential evaluates the impact of these assessment methods on sources of bias resulting from the nature of the patient patient outcomes. It found that contrast enhanced mag� population being investigated, the delay between index netic resonance angiography seemed to be more specific and reference tests, and the inability to blind observers. than computed tomography angiography (better at rul� Only one study compared patient outcomes. The rest ing out stenosis of 50% or more in a lower limb vessel) compared diagnostic “accuracy,” which can be hard to and more sensitive than duplex ultrasound (better at define in a clinically meaningful way, especially when

PHILBOARDMAN ruling in stenosis of 50% or more). Magnetic resonance data are presented by arterial segment rather than by angiography was also generally preferred by patients limb or by patient. R��elative sensitivities and specificities, Research, p 1257 over contrast angiography. So what do these results often with wide ranges, for various degrees of arterial Andrew W Bradbury Sampson mean for practising clinicians? stenosis, most commonly 50%—a level of disease with Gamgee professor of vascular In developed countries up to a fifth of the population limited biological or clinical relevance—are hard to fac� surgery and consultant vascular and endovascular surgeon over the age of 60 has lower limb peripheral arterial tor into everyday clinical decision making. In reality, Donald J Adam senior lecturer disease, as defined by absent pulses or a reduced ankle as pointed out by Collins and colleagues, the choice of and consultant vascular and brachial pressure index. A��bout a �q��uarter of these people imaging may be more influenced by patient preference endovascular surgeon, University Department of Vascular Surgery, have symptoms—most commonly intermittent claudi� and tolerance as well as the availability of the test. Heart of England NHS Foundation cation. This consists of pain in the leg (usually in the When a patient with peripheral arterial disease needs Trust, Solihull Hospital, Birmingham calf) on walking, as a result of atherosclerotic stenosis diagnostic imaging, it seems sensible to start with the B91 2JL ann.murray@heartofengland. or occlusion, usually of the superficial femoral artery simplest and safest modality, which is undoubtedly nhs.uk in the thigh.2 duplex ultrasound.1 2 Only if this proves insufficient Competing interests: None declared. Only a small minority of patients with ��intermittent should more sophisticated, potentially risky, and costly Provenance and peer review: claudication�� undergo imaging with a view to open sur� tests normally be considered. ��In practice, this is now Commissioned; not externally peer reviewed. gical (bypass, endarterectomy) or endovascular (angio‑ unusual given the quality of the machines used and the plasty, stenting) intervention. Most claudicants are skill of vascular technologists. BMJ 2007;334:1229-30 treated medically in primary3 or secondary care4—if Intra-arterial digital subtraction angiography is the doi: 10.1136/bmj.39244.344664.80 they are treated at all.5 In contrast, most patients with reference standard, but magnetic resonance angiography severe limb ischaemia (rest pain, tissue loss) undergo and computed tomographic angiography can provide imaging with a view to interventional treatment, usually more information and can be more accurate than ultra� by means of bypass surgery or angioplasty.6 7 sound.1 H�owever,�� in many cases the extra information Imaging studies are of little use in peripheral arte� and accuracy has little effect on patient management rial disease unless intervention is being considered and and outcome. The only study in the review by Collins the imaging results are likely to influence the choice and colleagues that compared patient outcomes found and nature of that intervention. In an era of “high tech” no significant difference between duplex ultrasound and medicine we sometimes forget that the purpose of imag� intra-arterial digital subtraction angiography�. ing is not just to obtain pleasing pictures but to answer In summary, the available data,1 supported by every� specific clinicalq uestions that have been thoughtfully day clinical experience, suggest that duplex ultrasound framed after undertaking a careful history, thorough is the only imaging test needed in most patients. If ultra� examination, and non-invasive assessments.8 �N��ot surpri� sound is not sufficient, then most clinicians would prob� singly, Collins and colleagues found that the availability ably choose m��agnetic resonance angiography rather of appropriate clinical data increased the accuracy and than computed tomographic angiography�� because it quality of imaging interpretation. is more versatile, more accurate, is not as affected by The�� imaging modality should be carefully chosen, in arterial calcification,1 8 and does not involve exposing an evidence based manner, so as to maximise the qual� patients to ionising radiation.9 10 ity and relevance of information obtained, minimise the Diagnostic imaging continues to evolve and improve risk and inconvenience to the patient, and make the best at an astonishing rate. There is�� a growing consensus

BMJ | 16 june 2007 | Volume 334 1229 EDITORIALS

that invasive techniques should not be used to visualise the implications for research into and treatment of intermittent claudication. J Vasc Surg 2006;44:432-3. the arterial system unless a therapeutic intervention is 5 Khan S, Flather M, Mister R, Delahunty N, Fowkes G, Bradbury A, et intended. Thus, diagnostic intra��-�arterial�� digital subtrac� al. Characteristics and treatments of patients with peripheral arterial disease referred to UK vascular clinics: results of a prospective registry. tion angiography�� is likely to become a thing of the past, Eur J Vasc Endovasc Surg 2007;33:442-50. with open and endovascular treatments for peripheral 6 Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, �F��orbes J�F��, et al; BASIL Trial Participants. Bypass versus angioplasty in severe ischaemia arterial disease being planned almost exclusively on the of the leg (BASIL): multicentre, randomised controlled trial. Lancet basis of duplex ultrasound and, where necessary, m��ag� 2005;366:1925-34. 11 12 7 Bradbury AW. Management of severe ischaemia of the leg. Br J Surg netic resonance angiography. 2006;93:1313-4. 8 Begelman SM, Jaff MR. Noninvasive diagnostic strategies for peripheral 1 Collins R, Burch J, Cranny G, Aguiar-Ibáñez R, Craig D, Wright K, et arterial disease. Cleve Clin J Med 2006;73(suppl 4):S22-9. al. Duplex ultrasonography, magnetic resonance angiography, and 9 Ouwendijk R, Kock MC, van Dijk LC, van Sambeek MR, Stijnen T, Hunink computed tomography angiography for diagnosis and assessment of MG. Vessel wall calcifications at multi-detector row CT angiography in symptomatic, lower limb peripheral arterial disease: systematic review. patients with peripheral arterial disease: effect on clinical utility and BMJ 2007 doi: 10.1136/bmj.39217.473275.55. clinical predictors. Radiology 2006;241:603-8. 2 Norgren L, Hiatt WR, Dormandy JA, ��Nehler �M��R, Harris KA, �F��ow�k��es �F�G; 10 Fleischmann D, Hallett RL, ��Rubin GD. CT angiography of peripheral TASC II Working Group. Inter-society consensus for the management arterial disease. J Vasc Interv Radiol 2006;17:3-26. of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 11 Kramer CM, Anderson JD. MRI of atherosclerosis: diagnosis and 2007;33(suppl 1):S1-75. monitoring therapy. Exp Rev Cardiovasc Ther 2007;5:69-80. 3 Burns P, Gough S, Bradbury AW. Management of peripheral arterial 12 Pavlovic C, Futamatsu H, Angiolillo DJ, Guzman LA, Wilke N, Siragusa D, disease in primary care. BMJ 2003;326:584-8. et al. Quantitative contrast enhanced magnetic resonance imaging for 4 Hobbs SD, Bradbury AW. The exercise versus angioplasty in the evaluation of peripheral arterial disease: a comparative study versus claudication trial (EXACT): reasons for recruitment failure and standard digital angiography. Int J Cardiovasc Imaging 2007;23:225-32.

Provision of primary care in different countries Priorities of patients should not be overpowered by economic and political incentives

Primary care has an important part to play within health� UK patients have an average of 4.5 consultations each care systems.1 The World Health Organization defines year, so these figures imply a per capita annual exposure the main aim of healthcare systems as the improvement to primary care physicians of around 60 minutes each of health, but it notes that financing should be fair and year—an increase of 28% in just five years.11 Bindman systems of care ought to respond to people’s expecta� and colleagues highlight a substantial variation in such tions.2 Countries whose healthcare delivery focuses on exposure between the three countries they studied—from the role of the specialist tend to fare less well in surveys 29.7 minutes each year in the US to 83.4 minutes each that take account of these three goals.3 Primary care year in Australia. seems to offer important advantages within healthcare Similar methods to those used by Bindman and col� systems in terms of cost containment, health status of leagues to define case mix have been used to investigate the population, and a range of other health related out� the relative contribution of social class and case mix in

PATRICK WARD/ALAMYPATRICK comes—the value of a strong primary care base within modelling the use of home visits in primary care set� Research, p 1261 national healthcare systems is recognised by WHO.4 tings.12 The methodological approach used in the current John L Campbell professor of How can cross national studies provide insight into the study to assess differences in case mix is sophisticated; it general practice and primary care optimal organisation of health care? draws on a diagnostic coding system developed at Johns Peninsula Medical School, St In this week’s BMJ, Bindman and colleagues5 use data Hopkins Hospital, which has been validated for use in Luke’s Campus, Exeter EX1 2LU [email protected] from national surveys in Australia, New Zealand, and primary care. It has the potential to compare case mix in Competing interests: None the United States to compare mix of patients, scope of primary care in countries that extensively use morbidity declared practice, and duration of visits in primary care. Previous coding systems, such as those of the International Clas� Provenance and peer review: studies have compared patient morbidity and patients’ sification of Disease orR EAD coding system. Commissioned; not externally peer expectations of care between countries.6 7 This study dif� A limitation of Bindman and colleagues’ study is reviewed. fers in that it examines case mix and exposure to primary that only administrative or preventive care codes were BMJ 2007;334:1230-1 care in three countries using rigorous and innovative ways recorded in up to 20% of consultations, and these were doi: 10.1136/bmj.39237.534560.80 to analyse large nationally representative datasets. excluded from the analysis. While the role that doc� In primary care, length of consultation has been pro� tors play in society varies in different countries, the posed as a marker of quality of care, with longer consul� authors are right to note that such consultations should tations increasing patients’ satisfaction and being more be included in the overall assessment of case mix. This comprehensive and more responsive to patients’ needs.8 9 would enhance the generalisability of the findings and Few studies have reported exposure to primary care in provide a more comprehensive overview of the contri� populations or have used such a measure to investigate bution of primary care to the healthcare system within differences between groups of individuals with regard the country. to the experience or outcome of health care. It may be surprising to general clinicians providing In the United Kingdom, a recent national survey of “comprehensive” first line care that 75% of the work� primary care provision10 reported a median consultation load of US primary care physicians’ comprises just 46 length of 13.3 minutes for general practitioners in 2003. conditions. Also, this number rose to only 57 conditions

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1 Starfield B. Primary care. Balancing health needs, services, and for family doctors in New Zealand, a country that is technology. New York: Oxford University Press, 1998. much more orientated towards primary care than the 2 World Health Organization. Health systems: improving performance. Geneva: WHO, 2000. www.who.int/whr/2000/en/. US, and which has healthcare structures similar to those 3 Davis K, Schoen C, Schoenbaum SC, Audet AJ, Doty MM, Holmgren AL, of the UK National Health Service. Some substantial et al. Mirror, mirror on the wall: an update on the quality of American health care through the patient’s lens. New York: Commonwealth differences were seen between national populations in Fund, 2006. www.cmwf.org/usr_doc/Davis_mirrormirror_915.pdf. primary care case mix—women in the US had lower 4 World Health Organization Health Evidence Network. What are the advantages and disadvantages of restructuring a health care system rates of attending primary care for gynaecological prob� to be more focussed on primary care services? Geneva, WHO, 2004. lems, but attendance for endocrine and cardiovascular 5 Bindman AB, Forrest CB, Britt H, Crampton P, Majeed A. Diagnostic problems was much higher in the US than in Australia scope of and exposure to primary care physicians in Australia, New Zealand, and the United States: cross sectional analysis of and New Zealand. Such observations may reflect dif� results from three national surveys. BMJ 2007 doi: 10.1136/ ferences between countries in access to care and in the bmj.39203.658970.55. 6 Wensing M, Baker R, Szecsenyi J, Grol R. Impact of national health gatekeeping role of family doctors, but they may also care systems on patient evaluations of general practice in Europe. result from cultural differences between populations Health Policy 2004;68:353-7. 7 Okkes IM, Polderman GO, Fryer GE, Yamada T, Bujak M, Oskam SK, in their interpretation of symptoms and in their use of et al. The role of family practice in different health care systems: a health services. comparison of reasons for encounter, diagnoses, and interventions in primary care populations in the Netherlands, Japan, Poland, and the Even in Western healthcare systems, inequalities United States. J Fam Pract 2002;51:72-3. in health status and experience of care exist between 8 Howie JGR, Porter AM, Heaney DJ, Hopton JL. Long to short consultation ratio: a proxy measure of quality of care for general individuals. Squandering of resources through failure practice. Br J Gen Pract 1991;41:48-54. to provide a strong primary care base within national 9 Wilson A, Childs S. The relationship between consultation length, process and outcomes in general practice: a systematic review. Br J health systems is likely to reinforce divisions within soci� Gen Pract 2002;52:1012-20. ety, worsen the health status of individuals, and create 10 Audit Commission for Local Authorities and the National Health Service in England and Wales. Transforming primary care: the role a healthcare system that is unresponsive to the needs of of primary care trusts in shaping and supporting general practice. the population. Cross national comparative studies have London: Audit Commission, 2004. www.wales.nhs.uk/documents/ TransformingPrimaryCare.pdf. the potential to inform the development of services, but 11 Gray DP. Forty-seven minutes a year for the patient. Br J Gen Pract they need to take account of the beliefs and values of the 1998;48:1816-7. 12 O’Sullivan C, Omar RZ, Forrest CB, Majeed A. Adjusting for case people served as well as the ambitions and resources of mix and social class in examining variation in home visits between their health professionals and politicians. practices. Fam Pract 2004;21:355-63.

Transition of care in children with chronic disease Healthcare teams need to adapt to change as much as patients and their families

In this week’s BMJ, a woman with cystic fibrosis ated with morbidity, mortality, and limitations to life’s describes her experience of living with the disease from options. Coping with these extra problems on top of childhood to adulthood.1 Among the many challenges the normal challenges of adolescence is an immense she describes is the “rocky road” of transition from pae� challenge, which is made worse by being cut off by the diatric to adult health care. She says that she ��would have paediatric care team that the patient knows and trusts. given anything to attend a transition clinic when she was Fundamental differences exist between paediatric 16 years old, instead of going straight to an adult clinic and adult chronic care. Paediatric care is often multidis� at another hospital. ciplinary, prescriptive, and family focused. It requires Cystic fibrosis was previously considered a lethal dis� parental direction and consent. Adult care tends to be order of childhood, but as survival improves, the need patient focused, and it encourages autonomy in making for continuous care into adulthood becomes more decisions about treatment and life choices. Professionals

SIMONFRASER/RVI/SPL important. For the past two decades the global cystic in adult care are familiar with the difficulties associated fibrosis community has recognised the importance of with sex, pregnancy, work, and raising a family in the PRACTICE, p 1270 transferring care from paediatric to adult services, and context of chronic ill health.3 Colin Wallis consultant has set an example for services in other chronic condi� A successful transition process has defined stages. respiratory paediatrician, Great tions to follow.2 Firstly, the needs and benefits of a move to adult care Ormond Street Hospital for Children NHS Trust, London WC1N 3JH Transition to adult care for any child with a chronic are explained and discussed with the young adult patient [email protected] life limiting illness should not consist of just transfer to and the parents. A combined clinic is then held where Competing interests: None a doctor who treats adults. It should be a clinical and the patient and family meet with the “receiving” team declared Provenance and peer review: psychosocial process. Adolescence is a time of great for a multidisciplinary handover. An orientation tour Commissioned; not externally change—a normal journey of transition from childhood of the adult centre is an important part of the journey. peer reviewed. to adulthood. It is a difficult and exciting time as shifts Finally, there is the last goodbye—a visit to ensure that occur in emotional attachments, autonomy, self iden� all aspects of transition have been covered.4 BMJ 2007;334:1231-2 doi: 10.1136/bmj.39232.425197.BE tity, sexuality, physical shape, philosophy of life, and Surveys show that patients and parents have a positive vocation. For those with a chronic illness, this devel� opinion of such transition clinics.5 The parents’ biggest opmental stage is complicated further as the teenager concern was whether their child would be able to care takes responsibility for care and faces problems associ� for their illness independently, although this concern

BMJ | 16 june 2007 | Volume 334 1231 EDITORIALS

was not always shared by the children. paediatric conditions? The case for chronic disorders Transition services have been developed for children with an advancing morbidity and the need for large with other chronic conditions, such as diabetes,6 renal multidisciplinary input is clear and these services have disease,7 and complex congenital heart disease,8 in addi� been adopted in many countries worldwide, such as tion to transplants recipients.9 The principles are similar, the United States, Australia, South Africa, and many although local resources and the underlying condition countries within Europe.12 However, the natural his� determine the details of care. tory of many childhood conditions has changed with In the United Kingdom, as in many countries, transi� modern treatment. For example, children with HIV tion occurs when patients are between 16 and 18 years find the transition particularly difficult as they move of age, and it ties in with the educational curriculum and into a world with few adolescents and a healthcare envi� social needs. Although timing is generally determined ronment mainly focused on the needs of homosexual by age, it may require review in people who are less men.13 And for some conditions there are no existing able to care for themselves as a result of mental capacity adult teams, such as immunodeficiency diseases like or severe ill health.10 chronic granulomatous disease. The hurdles for transition medicine lie as much with Some clinical teams and families remain reluctant to the healthcare teams as with the patients and their fami� buy into the concept of transition medicine.14 But the lies. The attitude towards transition and the relationship considerable financial and emotional input in caring between the paediatric and adult clinics is central to for the child with a chronic condition should not be success.11 Some paediatric units find it hard to let go of lost in a failed transition process. This is not just about children they have looked after for so long. But holding paediatric teams being unduly precious about the chil� on to patients who could benefit from the expertise of dren they have steered through 17 difficult years. This an adult orientated service causes as many problems as is about preventing adults looking back and saying, “I� treating transition just as an administrative event. would have given anything to attend a transition clinic Do we really need a transition service for all chronic when I was 16.”

Tamiflu and neuropsychiatric disturbance in adolescents The case is not proved but caution is advisable

In March 2007 the Japanese authorities advised against As seasonal prophylaxis, the protective efficacy was 74% prescribing oseltamivir (Tamiflu,R oche) to adolescents in healthy people aged 18-656 and even higher in frail aged 10-19 years.1 This unusually severe measure elderly people in residential care.8 resulted from the separate suicides of two 14 year olds The National Institute for Health and Clinical Excel� who jumped to their deaths while taking oseltamivir; 52 lence advises that oseltamivir should not be prescribed other deaths (14 in children or adolescents) have been for otherwise healthy people because the health gain in associated with the same drug. So far, similar action has this group is modest.4 6 However, oseltamivir is recom� not followed in Europe. When a regulatory authority mended for treatment and postexposure prophylaxis warns doctors not to prescribe a drug but decides in people who are at increased risk of complications not to retract its marketing authorisation prescribers because of age or comorbid conditions (box). This and patients are entitled to be concerned and a little restricted recommendation in the United Kingdom

comstockcomplete confused. has limited prescription of oseltamivir to only a few Oseltamivir is a sialic acid analogue that inhibits thousand people.9 In contrast, an estimated 45 million Simon R J Maxwell senior influenza typeA and type B neuraminidase, the viral patients have received oseltamivir worldwide.1 This has lecturer, ��Clinical Pharmacology Unit, University of Edinburgh, enzyme that allows the release of virus from infected been partly boosted by encouragement from the World Queen’s Medical Research Institute, cells. Its main licensed indications are the treatment of Health Organization, as a way to gain familiarity with Edinburgh EH16 4TJ flu, short termpostexposure�� prophylaxis after contact antiviral agents before the outbreak of a pandemic.10 [email protected] Competing interests: SRJM is with a diagnosed case of flu, and more prolonged (up to Several governments have been stockpiling supplies in a member of the technology six weeks) “seasonal” prophylaxis when flu is circulating preparation for such an event. appraisal committee at the in the community.�� The licence was extended in 2005 to So far, oseltamivir has been thought to be well tol� National Institute for Health and Clinical Excellence. include children aged 1-12 years. erated and safe. The most common adverse effect is Provenance and peer review: When used to treat otherwise healthy people, oselta� dose related nausea, which occurs twice as frequently Commissioned; not externally peer mivir reduces the duration of symptoms by 1-1.5 days as with placebo when used as prophylaxis.5 Post��‑� reviewed. if started within 48 hours of first symptoms, irrespective licensing monitoring has revealed very rare reports of of vaccination status, although it may be less effective in raised liver enzymes and hepatitis and of serious skin BMJ 2007;334:1232-3 2-5 doi: 10.1136/bmj.39240.497025.80 those with chronic diseases. It also provides a modest reactions, including Stevens-Johnson syndrome and reduction in complications such as pneumonia, otitis erythema multiforme.11 �However,�� the recent events in media in children, and hospital admission.4 5 As�� postex� Japan have prompted a reappraisal. posure prophylaxis, the protective efficacy of oseltamivir Before 2007, there had already been more than 100 was 80-90% in the family contacts of index cases.2 3 6 7 reports of neuropsychiatric events (including delirium,

1232 BMJ | 16 june 2007 | Volume 334 EDITORIALS

Patients at high risk of convulsions, and encephalitis) with oseltamivir in chil� benefit of treatment seems greater, although convinc� complications after flu dren, almost entirely from Japan, which has the highest ing evidence about reductions in hospital admission or • People over 65 years of usage of oseltamivir worldwide. However, these disturb� mortality is still awaited.�� In these groups, vaccination age ing events had to be seen in the context of the millions still offers a cost effective first line of defence.6 of prescriptions worldwide and the fact that abnormal • People with chronic 1 Japan issues Tamiflu warning after child deaths. Times 21 respiratory disease behaviour could also be due to flu or disease related March 2007. www.timesonline.co.uk/tol/news/world/asia/ (including asthma and complications. Indeed, a Food and Drug Administra� article1549260.ece. chronic obstructive tion (FDA) review of clinical trial and postmarketing 2 Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner DA, Nicholson pulmonary disease) KG. Effectiveness of neuraminidase inhibitors in treatment and data concluded that these events were not clearly drug prevention of influenza A and B: systematic review and meta- • Patients with related but might be related to higher rates of flu related analyses of randomised controlled trials. BMJ 2003;326:1235-40. cardiovascular disease 3 Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. encephalitis in Japan.12 Since last November, the FDA (excluding those with Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Health Technol Assess hypertension only) has required that doctors be warned that patients should be closely monitored for signs of abnormal behaviour 2003;7:1-182. • Patients with chronic 4 National Institute for Clinical Excellence. Guidance on the use of renal disease throughout the treatment period and the European zanamivir, oseltamivir and amantadine for the treatment of influenza. Medicine Evaluation Agency (EMEA) took similar Technology appraisal guidance 58. 2003. www.nice.org.uk/page. • Immunocompromised aspx?o=TA058guidance. patients steps in February. 5 Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. • People with diabetes The controversy about oseltamivir is a further Antivirals for influenza in healthy adults: systematic review. Lancet mellitus reminder that, although common adverse effects of a 2006;367:303-13. 6 National Institute for Clinical Excellence. Guidance on the use drug may emerge in prelicensing studies, the detec� of oseltamivir and amantadine for the prophylaxis of influenza. tion of rarer and potentially more serious events has Technology appraisal 67. 2003. www.nice.org.uk/page. aspx?o=TA067guidance. to await exposure of large numbers of patients. In the 7 Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of UK, oseltamivir is a “black triangle” drug, so it remains oseltamivir treatment on influenza-related lower respiratory tract under more intensive surveillance. Doctors and other complications and hospitalizations. Arch Intern Med 2003;163:1667- 72. healthcare professionals should report all minor as well 8 Peters PH Jr, Gravenstein S, Norwood P, De Bock V, Van Couter A, as serious adverse events via the yellow card scheme. Gibbens M, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc In the light of these concerns how should prescrib� 2001;49:1025-31. ers proceed? There seems little doubt that oseltamivir 9 Department of Health. Prescription cost analysis. www.dh.gov.uk/ reduces the number and seriousness of flu episodes en/PublicationsAndStatistics/Statistics/StatisticalWorkAreas/ StatisticalHealthCare/DH_4086488. when used as treatment and prophylaxis. However, 10 WHO. Global agenda on influenza surveillance and control. www. the impact of such events in otherwise healthy people who.int/csr/disease/influenza/globalagenda/en/index.html. is usually modest and of short duration. They�� should be 11 European Medicines Evaluation Agency. Scientific discussion. 2006. www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/Tamiflu- encouraged to use conservative strategies such as resting, H-402-II-20.pdf. increasing fluid intake, and taking simple analgesics 12 Food and Drug Administration, Center for Drug Evaluation and Research. Pediatric safety update for Tamiflu. Pediatric Advisory and over the counter symptomatic remedies. ��In Committee meeting, 18 November 2005. www.fda.gov/ohrms/ people at higher risk of serious complications the potential dockets/ac/05/briefing/2005-4180b_06_06_summary.pdf.

Rosiglitazone and implications for pharmacovigilance Postsurveillance data should be systematically collected and publicly available

On 21 May 2007, the New England Journal of Medicine increase over the previous year.2 However, the recently published a meta-analysis of 42 trials of rosiglitazone published meta-analysis raises serious questions about (Avandia, GlaxoSmithKline) for treating type 2 diabe� the drug’s safety. tes mellitus. It found that the drug was associated with Meta-analyses have unique strengths and weaknesses an increased risk of myocardial infarction (odds ratio and this one is no exception.3 Its singular strength is the 1.43; 95% confidence interval 1.03 to 1.98; P=0.03) and statistical power generated by data on 15 560 patients death from cardiovascular causes (1.64; 0.98 to 2.74; from published and unpublished trials. However, it P=0.06).1 includes clinically heterogeneous trials and criteria used CUSTOMMEDICAL STOCKPHOTO/SPL Rosiglitazone, a thiazolidinedione, is an agonist at the by individual trials to classify adverse events are some� Dhruv Kazi internal medicine peroxisome-proliferator activated receptors in cell nuclei. what unclear. Only summary data are available in the physician, London School of These receptors modulate the expression of a host of public domain—for example, whether or not a person Economics, London WC2A 2AE genes, and glycaemic control is achieved primarily had a myocardial infarction, not when it occurred—which [email protected] through increased insulin sensitivity in peripheral tissues. makes time to event analyses impossible. Also, the total Competing interests: None declared. Rosiglitazone was approved by the US Food and Drug number of adverse events was small, so that misclassifi� Provenance and peer review: Administration (FDA) in 1999 and by the centralised cation of a few events could alter the conclusions. Commissioned; not externally peer process of the European Medicines Agency (EMEA) in In response to the concerns raised by this meta-analy� reviewed. 2000. Its popularity has increased steadily, with more sis, an unplanned interim analysis of a large, manufacture BMJ 2007;334:1233-4 than one million prescriptions written in the one year sponsored, randomised, open label, non-inferiority trial doi: 10.1136/bmj.39245.502546.BE period ending March 2006 in England alone—a 22% specifically designed to investigate the cardiovascular

BMJ | 16 june 2007 | Volume 334 1233 EDITORIALS

safety of rosiglitazone was recently released.4 Compared evaluation.12 This would involve a systematic effort to with patients taking metformin and a sulphonylurea, monitor the safety and efficacy of a drug before and people taking a regimen that included rosiglitazone had after approval using data from well designed clinical no significant increase in the risk of myocardial infarc� trials to inform ongoing risk-benefit analyses. This tion (hazard ratio 1.16,�� 0.75 to 1.81), although they�� had process could be made more systematic by requiring a significantly increased risk of heart failure ��2.24,( 1.27 regulatory authorities to periodically and independently to 3.97).�� When�� these new data are added to the trials in re-evaluate all data gathered after approval for all new the previous meta-analysis, rosiglitazone is associated molecular entities—particularly drugs with high sales. with an increased risk of myocardial infarction (odds In addition, the lack of transparency in the current ratio, 1.33; 1.02 to 1.72).5 system needs to be dealt with. There should be a legal To summarise, the meta-analyses show a significantly requirement for all phase II-IV trials to be registered increased risk for myocardial infarction, whereas several in a centralised database, such as the National Library individual prospective trials do not. More data would of Medicine’s clinicaltrials.gov or an equivalent. Com� certainly help to clarify the matter, but the emerging plete datasets from these trials, systematic analyses of safety concerns question the prudence of continuing the results, and reports of periodic evaluations by the ongoing trials. Notwithstanding the ethical concerns, regulatory agencies must be publicly available. it may be impossible to prevent an exodus of patients A radical change is needed in the culture of existing from these trials in light of the ongoing “trial by media” regulatory institutions that regard postmarketing surveil� of the drug. lance as their secondary mandate. This will require sys� The broader question is how this reflects on regulatory tematic rethinking of the existing regulatory and funding processes used to monitor drug safety. Postmarketing processes, and expediting changes currently in the pipe� surveillance, or pharmacovigilance, remains the weak� line.13 Progress will entail empowering the regulatory est link in the regulatory process on both sides of the agencies with additional authority and resources. Atlantic. The current approach—the FDA’s adverse event The manufacturer and the FDA will share the spot� reporting system and the European EudraVigilance pro� light as congressional investigation into the matter starts. gramme—relies heavily on passive surveillance, and it In the meantime, what are the implications for patients is based on reports of unusual adverse events from con� currently on rosiglitazone? Doctors will need to revisit sumers, practitioners, manufacturers, and national regu� the indication for the drug on a case by case basis, bear� latory authorities. At best, this creates a case series, one ing in mind that several alternatives are cheaper, sup� of the weakest forms of epidemiological evidence,6 that ported by robust evidence, and now perhaps safer.14 would be insensitive to an increase in common events The decision to switch drugs must be tempered by the like myocardial infarcts in diabetics. fragility of the available evidence and the risks associ� Alternatively, the regulatory authorities may require ated with altering patients’ medical regimens. Needless systematic phase IV trials after market authorisation, to say, the ongoing use of rosiglitazone merits careful but these are often not completed in a timely manner. deliberation. In the United States, completion dropped from 62% 1 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial in the 1970s to 24% in recent years,6 and the FDA is infarction and death from cardiovascular causes. N Engl J Med Published online 21 May 2007. ill equipped to act against defaulters. As of September 2 National Institute for Health and Clinical Excellence. NICE 2006, 930 (74%) of the 1259 postmarket studies were implementation uptake report: glitazones (rosiglitazone and 7 pioglitazone). 2007. www.nice.org.uk/page.aspx?o=423524. pending or delayed. 3 Eysenck HJ. Meta-analysis and its problems. BMJ 1994;309:789-92. This results in a fractured regulatory process, where 4 Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones N, et al. Rosiglitazone evaluated for cardiovascular outcomes—an interim the preapproval phase is marked by stringent require� analysis. N Engl J Med Published online 5 June 2007. ments for safety and efficacy data, but performance in 5 Psaty BM, Furberg CD. The record of rosiglitazone and the risk of myocardial infarction. N Engl J Med Published online 5 June 2007. postmarketing surveillance falls short of the standards 6 US Senate. Testimony of Bruce M Psaty, before the House Committee on the agencies set for themselves. This is exemplified by Energy and Commerce subcommittee on oversight and investigations. 2007. http://energycommerce.house.gov/cmte_mtgs/110-oi- the case of rosiglitazone. Rosiglitazone comes from a hrg.032207.Psaty-testimony.pdf. family of drugs with well documented side effects,8 9 7 Food and Drug Administration. Report on the performance of drug and biologic firms conducting postmarketing commitment studies; and itself is associated with increased heart failure, anae� availability. Federal Register 2007;72:5069-70. mia, and raised low density lipoprotein concentration. 8 Gale EA. Lessons from the glitazones: a story of drug development. Lancet 2001;357:1870-5. However, postmarketing safety data seven years after 9 Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major regulatory approval consist of a patchwork of hetero� adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-6. geneous manufacturer sponsored trials, many of which 10 GlaxoSmithKline. Study no. ZM2005/00181/01. Avandia are unpublished. Of note, a similar meta-analysis sub� cardiovascular event modeling project. http://ctr.gsk.co.uk/ Summary/Rosiglitazone/III_CVmodeling.pdf. mitted by the manufacturer to the EMEA and the FDA 11 European Medicines Agency. European public assessment report for in August 2006 showed an increased risk in ischaemic authorised medicinal products for human use. Avandia. 2007. www. 10 emea.europa.eu/humandocs/Humans/EPAR/avandia/avandia. events (hazard�� ratio, 1.31, 1.01 to 1.70).� The EMEA html. updated the product label of the drug,11 but no specific 12 Psaty BM, Burke SP. Protecting the health of the public—Institute of Medicine recommendations on drug safety. N Engl J Med communication to healthcare professionals was issued. 2006;355:1753-5. The FDA did neither. 13 European Medicines Agency. Work programme for European Medicines Agency. London: EMEA, 2007:20-2. The system needs to be fixed. The Institute of 14 Nathan DM. Rosiglitazone and cardiotoxicity—weighing the evidence. Medicine recommends a life cycle approach to drug N Engl J Med Published online 5 June 2007.

1234 BMJ | 16 june 2007 | Volume 334 We select the letters for these pages from the rapid responses posted on bmj.com favouring those received within five days of publication of the article to which they letters refer. Letters are thus an early selection of rapid responses on a particular topic. Readers should consult the website for the full list of responses and any authors’ replies, which usually arrive after our selection.

remotely near industry budgets, but doctors Manchester, Manchester M20 4BX interested in the health of the public have [email protected] to develop expertise on the ways of big Competing interests: APG is a rugby referee who took part in the RugbySmart campaign. business and use this expertise in informing individual shareholders on the wider 1� Quarrie KL, Gianotti SM, Hopkins WG, Hume PA. Effect of nationwide injury prevention programme on serious societal implications of their investments. spinal injuries in New Zealand rugby union: ecological Joseph M Barry clinical professor, Department of Public study. BMJ 2007;334:1150-3. (2 June.) Health and Primary Care, Trinity College Centre for Health 2� Noakes TD, Draper CE. Preventing spinal cord injuries in Sciences, AMNCH Tallaght, Dublin 24, Republic of Ireland rugby union. BMJ 2007;334:1122-3. (2 June.) 3� Fuller CW, Brooks JH, Cancea RJ, Hall J, Kemp SP. Contact [email protected] COMSTOCK COMPLETE COMSTOCK events in rugby union and their propensity to cause Tom O’Dowd professor of general practice injury. Br J Sports Med 2007; May 18. [Epub ahead of Doctors and alcohol Competing interests: None declared. print] PMID: 17513332.

1� Richards T. Europe on the rocks. BMJ 2007;334:1142. Investing in alcohol is no longer (2 June.) 2� McKee M. A European alcohol strategy: will the PTSD in Northern Ireland responsible opportunity be missed? BMJ 2006;333:871-2. 3� Babor T, Caetano R, Casswell, S, Edwards G, Giesbrecht Tell us more “Doctors are stalwart drinkers,” says N, Graham K, et al. Alcohol: no ordinary commodity. Richards, calling on doctors to do more Research and public policy. Oxford and London: Oxford Duffy et al provide evidence for the University Press, 2003. to tackle alcohol abuse.1 Doctors are also effectiveness of cognitive therapy in post- stalwart investors and must begin to use traumatic stress disorder (PTSD) in the their financial clout as shareholders to Safer play in rugby context of terrorism and civil conflict in remove alcohol from their portfolios. Northern Ireland.1 More information would Last autumn, the multinational drinks Time to address safety have been helpful to interpret the results. industry used its political, business, and in the tackle No patients were started on medications financial lobbying muscle to subvert the during the trial. However, 52% in the European Commission’s attempts to bring As an amateur rugby referee who spent immediate therapy group were taking forward an alcohol strategy based on public the 2005 season refereeing in New Zealand antidepressants already. When were these health principles.2 In the past, the public and took part in the RugbySmart campaign initiated in relation to the trial? Also, health agenda has relied solely on evidence I was interested to read the analysis were any changes to the antidepressant to effect political change. This worked when by Quarrie et al of its impact on spinal dose allowed during the trial? Over 70% elected politicians had a stronger influence injuries.1 As they point out, most of the in the immediate therapy group had on society. The business corporations have reduction in injuries was accounted for comorbid major depression. The effect of now become bigger players where the by a reduction in scrum related injuries. antidepressant initiation just before the trial measure of success is profit. Health policy Whether a similar campaign would be or dose changes may be partly responsible has to accommodate to this change and equally effective in Britain is unclear, given for the improvement in this group’s will have to engage shareholders directly the recent 2006 changes in the scrum symptoms. to get them to avoid alcohol at both engagement procedure; but as pointed The percentages for the overall manufacturing and the sometimes forgotten out in the accompanying editorial it can effectiveness of cognitive therapy are retailing levels. certainly do no harm.2 the combined scores of the immediate Leadership is required from doctors, The paper highlighted another area of treatment and waiting list control groups. who are often the first witnesses of alcohol concern; seven out of eight spinal injuries This makes them uncontrolled scores. The related harm. This can be exercised by occurred at the tackle. Over the past 10 authors are not comparing two groups of refusing to hold shares in alcohol companies years there has been an increase in the high patients, one receiving therapy and the and by instructing fund managers to set impact, chest high “ball and all” tackle. This other not receiving therapy. up and seek non-alcohol based portfolios. area of the game is now associated with the The follow-up mean scores in table It is time to include the manufacture most injuries,3 and this type of tackle puts 3 have been taken at either four or and importantly the sale of alcohol as an the tackling player at risk of a head on torso 12 months. As a clinician, I would be unworthy and unethical way of making collision and spinal injury. particularly interested in information about money for the individual investor. Most Instead of further debates over banning the maintenance of gains at 12 months. doctors would not knowingly invest in the scrum we should concentrate on This is not clear from the table. If gains seen tobacco companies, and, although no level improving the safety at the tackle area by at four months are lost by 12 months, this of tobacco use is safe, alcohol is no ordinary legislation and educational initiatives similar then raises questions about whether booster commodity either3 and even small amounts to those described by Quarrie et al. sessions are indicated. can cause catastrophic harm. Alastair P Greystoke research fellow, medical oncology Finally, the therapist effect is important. Advocacy budgets will never come Paterson Institute of Cancer Research, University of It would be interesting to look at whether

BMJ | 16 june 2007 | Volume 334 1235 letters

this difference in patient scores is related to of myocardial infarction and an increase in gained and facilitating their re-entry into the the type of qualification in cognitive therapy cardiovascular deaths?1 system. that the therapists had. Recent research has The reduction in diabetes related end At the moment UK doctors working shown that formal post-qualification training points, mortality and stroke from using overseas cost the UK government nothing. in cognitive therapy is associated with metformin is not explicable on the basis of The government could recognise this competence.2 glycaemic control.2 by helping to pay off debts from student Adarsh Shetty specialist registrar in general adult psychiatry The data of UKPDS 33, which compared loans and help with the General Medical Psychiatric Unit, Derby City Hospital, Derby DE22 3NE tight glycaemic control with sulphonylureas Council’s registration fees, etc. This [email protected] or insulin with conventional treatment, money could come out of the overseas Competing interests: None declared. showed little benefit from tight control.3 aid budget. 1� Duffy M, Gillespie K, Clark DM. Post-traumatic stress The outcomes that did show some clinical Some organisations such as the BMA disorder in the context of terrorism and other civil conflict in Northern Ireland: randomised controlled trial. benefit were cataract extractions, retinal and Medical Protection Society recognise BMJ 2007;334:1147-50. (2 June.) photocoagulation, and non-fatal myocardial overseas service by offering either free or 2� Brosan L, Reynolds S, Moore RG. Factors associated with competence in cognitive therapists. Behav Cognitive infarction and all cause mortality—that is, heavily discounted membership to medical Psychother 2007;35:179-90. if you can call absolute risk reductions of missionaries and NGO volunteers. between 1 and 3 per 1000 patient years as Andrew L Perkins former medical missionary, Westoning, being clinically relevant. Bedfordshire MK45 5JD [email protected] Skin biopsy The wonder with drug licensing is Competing interests: ALP was a medical missionary in Mali, West Africa. Watch out for digital nerves that we continue to accept surrogate end points in trials to license new treatments 1� Mabey D. Improving health for the world’s poor. BMJ As a hand surgeon, I was concerned about for conditions for which we already have 2007;334:1126. (2 June.) the bottom right picture in figure 3 of the treatments. Show me better data or accept article by Lauria and Lombardi, which that the control of blood glucose means Trials and electronic records seems to show that a skin biopsy had been metformin--anything else is merely for taken from the radiovolar skin of the left symptom control. A frightening industry index finger.1 In the summary points box it Illtyd R Thomas general practitioner, Swansea SA1 5LF proposal was suggested that a skin biopsy was easy [email protected] and almost painless. Furthermore, nowhere Competing interests: IRT has coauthored with Adrian The National Care Record Service (CRS), if Edwards, Glyn Elwin, and Rhys Williams a paper on was there any indication that potential explaining risk information over the internet to patients with it is ever deployed, certainly offers amazing injuries could be caused by the use of this diabetes, which was funded by the BMJ Group. potential for pharmaceutical research. The technique. Skin biopsy as indicated above whole COX2/NSAID debacle could have 1� Tanne JH. Study indicates diabetes drug linked to carries a high risk of causing a digital nerve cardiovascular death. BMJ 2007;334:1073. (26 May.) been rapidly resolved by access to the injury leading to a neuroma causing chronic doi: 10.1136/bmj.39224.364630.DB complete prescription records of 55 million 2� Effect of intensive blood-glucose control with metformin pain, which may require reconstructive on complications in overweight patients with type 2 people. surgery. If volar digital skin biopsies are diabetes (UKPDS 34). Lancet 1998;352:854-65. But this article sent shudders down my 3 Intensive blood-glucose control with sulphonylureas required then it is much safer to harvest or insulin compared with conventional treatment and spine about how the Association of the these in the midline of the finger, but risks of complications in patients with type 2 diabetes British Pharmaceutical Industry would like patients should be warned of the potential (UKPDS 33). Lancet 1998;352:837-53. to use the service.1 Dr Barker is quoted nerve injury and neuroma risk as important as saying it would allow drug companies nerves are only a few millimetres under the Helping the world’s poor to easily identify patients fitting a trial’s skin surface on fingers. inclusion and exclusion criteria. Bo Povlsen consultant orthopaedic surgeon, Guy’s Hospital, Let’s help doctors work Not using anonymised data, it wouldn’t. London SE1 7EH [email protected] in the third world I suppose it might tell you how many Competing interests: None declared. potential candidates there were, but that 1� Lauria G, Lombardi R. Skin biopsy: a new tool Surely it is not beyond the wit of our shouldn’t be too hard to figure out anyway. for diagnosing peripheral neuropathy. BMJ profession to devise a scheme that will make Anonymised data use for adverse events 2007;334:1159-62. (2 June.). it easier for UK health professionals to work surveillance is one thing; non-anonymised overseas either as missionaries, volunteers data to identify potential trial candidates, Rosiglitazone and heart deaths with non-governmental organisations presumably followed by a direct approach (NGOs), or in other “bona fide” set-ups. to invite them to join a drug trial, are Glycaemic control is a myth Some of the issues Mabey raises also affect another matter entirely. UK doctors wanting to take career breaks in This use is clearly in conflict with Tight control of HbA1c levels has been the United Kingdom.1 current data protection legislation—but Dr enshrined in the QOF (quality and We need to devise a way that UK doctors Barker should realise this. So why did he outcomes framework) of the new general working overseas can be part of some form propose it? practitioner contract as being an evidence of revalidation. We have an oversupply of Matthew L Grove consultant rheumatologist, North based proposal. Multiple drugs are licensed doctors at the moment trying to get into Tyneside General Hospital, North Shields NE29 8NH [email protected] on the understanding that they reduce the Modernising Medical Careers (MMC) Competing interests: None declared. HbA1c levels and that this is a good thing. process. Allowing some to opt out to 1� Butcher J. UK will lose clinical trials if electronic records So should it surprise us that a meta-analysis work overseas should be encouraged by system is delayed, ABPI warns. BMJ 2007;334:1132. of trials of rosiglitazone shows a raised risk recognising the experience they will have (2 June.)

1236 BMJ | 16 june 2007 | Volume 334 For the full versions of articles in this section see bmj.com UK NEWS NICE reviews its guidance on use of anti-TNF drugs for arthritis, p 1238 news World NEWS US�� parents tak�e�� governm�ent�� to court over MMR�� vaccine,�� p 124�1� bmj.com R��esearchers warn of possibl�e�� risk�s�� to chil�dren�� from new antiepil�eps��y drugs��

FDA places “black box” warning on antidiabetes drugs Janice Hopkins Tanne New York accompanying editorial in the New The US Food and Drug England Journal of Medicine (doi: Administration has asked the 10.1056/NEJMoa072761). makers of two antidiabetes John Buse, of the University of drugs—rosiglitazone (marketed as North Carolina, and the incoming Avandia), made by GlaxoSmithKline, president of the American Diabetes and pioglitazone (Actos), made Association, told the hearing that by Takeda—to place “black box” SmithKlineBeecham (now part warnings, the most serious kind, on of GlaxoSmithKline) had tried to their labels. intimidate him when he spoke The new labels warn of an out with his concerns about increased risk of congestive heart rosiglitazone’s cardiovascular safety. failure. Andrew von Eschenbach, the Dr Buse said that he had spoken FDA’s commissioner, announced the at least twice in June 1999 about warning at a hearing of the US House “a trend toward increases in of Representatives’ Committee on serious cardiovascular events and Oversight and Government Reform cardiovascular deaths with Avandia last week to examine the FDA’s as compared to active comparators.” role in evaluating the safety of He said that employees of s

rosiglitazone. SmithKlineBeecham had told him r The new labels do not address the in telephone calls that “there were question of whether these drugs some in the company who felt that pose an increased risk of heart my actions were scurrilous enough to t Padgett/Reutet

attacks and strokes. attempt to hold me liable for a loss in r

The cardiovascular risk was market capitalisation [share value].” Robe raised last month by an article and See Editorial, p 1233 Commissioner Andrew von Eschenbach announced the warnings last week Russian clinical research is threatened by ban Vasiliy Vlassov Moscow document but say that they are carrying out do with the struggle to control this growing Russia’s Federal Customs Service has blocked orders. industry. the export from Russia of all human biologi- The decision threatens dozens of clinical Two recent speeches in Russia promoted cal materials, from hair to tissue and blood trials in Russia, because doctors and scien- the idea that Western countries could be samples. tists need to send many samples abroad to developing weapons that would affect spe- An article in the Russian online news- be tested. About two thirds of trials in Russia cific ethnic groups. In early June Mikhail paper Kommersant says that the decision is depend on European labo- Zurabov, Russia’s min- thought to have arisen from a report sub- ratory services, and about The export of materials for ister of health and social mitted to President Vladimir Putin by the a half of trials may be clinical research is forbidden development, said that Federal Security Service (formerly the KGB), stopped because they rely until further notice the development of a which warned of the possible development on centralised testing. genetic weapon against by Western countries of genetic biological The decision also threatens hundreds of Russia is technically feasible. The next day weapons against particular nations (www. patients in Russia who rely on foreign tests Andrei Belianinov, head of the Federal Cus- kommersant.ru/doc-y.html?docId=769777 for tissue compatibility and such like. toms Service, was quoted in an interview as &issueId=36291). The clinical trials industry is expanding saying that the transfer of biomaterials from From the end of May the export of materi- rapidly in Russia and is thought to be worth Russia was equivalent to the “genocide of our als for clinical research and samples of blood between $100m (£50m; €75m) and $150m nation.” Banning such exports was needed and tissue is forbidden until further notice. a year. The government’s decision to ban for the “prevention of crime,” he said (Med- Customs officers do not cite any specific biological exports may have something to itsinskaia Gazeta 6 Jun, p 5).

BMJ | 16 June 2007 | Volume 334 1237 NEWS

Gates Foundation NHS IT system must use unique funds new institute for global health data identifiers to achieve potential Peter Moszynski London Susan Mayor London is the research and development advisory The Bill and Melinda Gates Foundation has The new NHS national programme for infor- group to Connecting for Health, the agency funded a research centre at the University mation technology (IT) must have research developing the network, commissioned four of Washington in Seattle to help guide inter- built in as a core task, says a report published simulated research exercises. These exercises national policy making by providing high this week. And it must use unique identifiers were designed to model interventional clini- quality data and analysis of health needs and for each patient to enable data from different cal trials, surveillance, prospective tracking outcomes. The Institute for Health Metrics sources to be linked at the level of individual of an identified cohort, and observational and Evaluation, which received a grant of patients if it is to achieve its huge potential epidemiological research. $105m (£53m; €80m) from the foundation, for clinical research. On the basis of their experience in the will also assess the performance of health Researchers produced the recommenda- simulated exercises, the advisory group rec- programmes around the world. tions after using simulations of clinical stud- ommended that the IT system should make “Health policy must be based on evi- ies to test the system. it mandatory to use unique dence, not speculation,” said Tachi Yamada, The programme—the “Pulling information patient identifiers. They president of the foundation’s global health world’s largest IT system—is together from different proposed that use of the programme. designed to link different sources for a patient will NHS number or its equiva- “There has been a huge increase in computer systems across require a unique identifier” lent should be mandatory resources for global health in recent years,” the NHS, including an NHS in all key NHS records and Dr Yamada said, “and it’s essential to evalu- care records service that will allow staff from activities, including laboratory records. Cur- ate the impact of these investments.” different organisations to access the records rently the use of patient identifiers is recom- The institute’s brief is to provide “high of patients anywhere in England. mended but not mandatory. quality and timely information on health It has been notorious for its delays and Ian Diamond, chief executive of the UK so that policy makers, researchers, donors, overspends (BMJ 2007;334;815, 21 Apr); but Economic and Social Research Council and practitioners, local decision makers, and the establishment of connections between chairman of the advisory group, said: “To build others can better allocate limited resources different NHS databases, such as those hold- a complete picture of each patient’s health and to achieve optimal results.” ing primary care records and cancer registry care, data linkage at an individual patient level It will be directed by Christopher Murray, records, could enable researchers to explore will be needed. Pulling information together who was previously director of the Harvard a wide range of trends and associations. from different sources for a patient will require University Initiative for Global Health and is To clarify the potential for the use of a unique identifier for each patient.” a former senior official at the World Health patients’ data from the new IT system, the Report of Research Simulations is available at www. Organization. UK Clinical Research Collaboration, which ukcrc.org. NICE reviews its guidance against sequential use of anti-TNF drugs for arthritis Susan Mayor London occasions one month apart and who The National Institute for Health have undergone trials of two disease and Clinical Excellence (NICE), the modifying antirheumatic drugs, independent body that advises the including methotrexate (unless NHS in England and Wales on use of contraindicated). The appraisal said treatments, has agreed to review its that treatment with TNF-α inhibitors draft guidance against the sequential should be continued only if there use of different tumour necrosis was an adequate response—defined factor α (TNF-α) inhibitors in patients as an improvement in the disease with rheumatoid arthritis, after an activity score of 1.2 points or more— appeal from a group representing at six months after treatment started. patients. However, NICE recommended In its appraisal published in against the use of a second TNF- November 2006 NICE recommended α inhibitor if a patient had “an the TNF-α inhibitors adalimumab, inadequate initial response or etanercept, and infliximab as options experienced loss of response later lamy A in the treatment of adults who during treatment with a TNF-α have active rheumatoid arthritis as inhibitor.” determined by a disease activity The institute received six appeals

JackSullivan/ score >5.1 confirmed on at least two against the appraisal from the

1238 BMJ | 16 June 2007 | Volume 334 NEWS s ell/Pano ss J B Ru B J Severely malnourished children at a Médecins Sans Frontières therapeutic feeding centre in Huambo province, Angola Community care could prevent deaths of thousands of severely malnourished children John Zarocostas Geneva complications, could help malnutrition, most of whom severe acute malnutrition,” An innovative way of treating prevent the deaths of hundreds live in South Asia and sub- WHO says. severe acute malnutrition, of thousands of children, UN Saharan Africa, says the World Children with severe acute combining timely detection and agencies say. Health Organization, and malnutrition are five to 20 community based care with Worldwide about 20 million about one million die from the times more likely than well traditional hospital treatment children under the age of condition every year. nourished children to die, for children with medical 5 years have severe acute The new approach has WHO estimates show. already greatly improved Margaret Chan, WHO’s survival of children with director general, said, “It is NICE reviews its guidance against sequential use of anti-TNF drugs for arthritis severe acute malnutrition in urgent that this approach, emergencies in countries such along with preventive action, Arthritis and Musculoskeletal that was based on 629 patients as Ethiopia, Malawi, Niger, and be added to the list of cost Alliance (an umbrella group who received a second TNF used Sudan, the agencies noted. effective interventions being representing people with arthritis, evidence on probability of response Evidence shows that about used to improve nutrition and professional bodies and research and duration of sequential treatment three quarters of children with reduce child mortality.” organisations in the field of arthritis), to investigate the cost effectiveness severe acute malnutrition Ready to use therapeutic the National Rheumatoid Arthritis of this approach. can be treated at home with foods “have proven very Society, the Royal College of Nursing, In its appeal the alliance reported, highly fortified, ready to effective in addressing severe and the drug companies making “The results suggest that a second use therapeutic foods, says acute malnutrition in children,” the three TNF-α inhibitors under TNF is similarly cost effective to a a joint statement issued last said Ann Veneman, executive consideration, Abbott Laboratories, first TNF.” week by WHO, the World director of Unicef. “So these Schering-Plough, and Wyeth. The appeal panel met in April, Food Programme, the United interventions are an important In its appeal the alliance reported and it announced this week Nations’ standing committee on tool in reducing child a study that looked at the effect of that NICE’s health technology nutrition, and Unicef. mortality.” allowing patients who withdrew appraisal committee had been “Severe acute malnutrition is Such foods are soft or from their first TNF treatment to “unreasonable” in deciding, on defined by a very low weight crushable and can be eaten receive a second TNF (sequential the evidence presented, to deny for height, by visible severe easily without water by treatment). In a previous study the sequential treatment. wasting, or by the presence children from the age of 6 lack of data on patients receiving a The appeal panel’s decision is of nutritional oedema . . . In months. second TNF had made this difficult available at http://guidance.nice. children aged 6-59 months, an Community-Based Management of to analyse. However, a new analysis org.uk/page.aspx?o=207026. arm circumference less than Severe Acute Malnutrition is available 110 mm is also indicative of at www.who.int.

BMJ | 16 June 2007 | Volume 334 1239 NEWS

Women should be Strike cripples health followed for longer after breast cancer services in South Africa Susan Mayor London Pat Sidley Johannesburg other hospital staff across the country, Women who undergo breast conserving Some 600 nurses have been fired from from striking, many of them chanting and surgery for early breast cancer should be South Africa’s public hospitals for taking dancing angrily outside their hospitals. followed up for much longer than the three part in a large civil service strike that has Media reports have claimed that to five years recommended in current guide- crippled many hospitals, schools, and other patients have died because of the lack lines, warns a study published this week. The government services. of ambulances or because hospitals are study shows that relapses can occur at least The strike, which is largely about pay and providing only limited services. Patients 10 years after initial treatment. conditions but also signals civil servants’ with HIV or AIDS and tuberculosis are The study, published in the British Journal opposition to the government’s economic also being denied their regular treatment of Cancer, analysed relapses in 1312 women policy, has led to many health services because of clinic closures, they say. with early stage breast cancer who underwent effectively shutting down, while others are The Chris Hani Baragwanath Hospital, breast conserving surgery and postoperative taking only the most critically ill patients. one of the largest hospitals in the southern radiotherapy between 1991 and 1998 and The dismissal of the nurses has added new hemisphere, has been forced to fly who were followed up at two centres in Edin- impetus to the strike, which has been running premature and sick babies in incubators by burgh (doi: 10.1038/sj.bjc.6603815). Analysis for two weeks and shows no signs of ending. helicopters to private facilities. Hundreds of the 110 treatable relapses showed that they Nurses, the government maintains, are of critically ill patients have also been occurred in 1% to 1.5% of the women in each emergency workers and are not allowed transferred from public to private hospitals, year of the follow-up period. to strike. However, this has not stopped for which the state will have to pay. But different types of relapse varied in tens of thousands of them, together with The government has sent army personnel their time scales. The incidence of metastatic relapse peaked at just over 3% a year at two to three years after initial surgery and Mortality from 12 top diseases than women do, because they tend remained at just over 2% a year for up to to have heart attacks and strokes earlier than five years before decreasing. In contrast, the causes in US is still women do. incidence of locoregional relapse remained “The years of potential life lost [to stroke] constant at 1% to 1.5% over the whole of the higher among men before the age of 75 is 20% higher for men follow-up period. than for women, ie men tend to die of Guidelines in North America and the Roger Dobson Abergavenny stroke at younger ages than women,” write United Kingdom recommend that follow-up Mortality is higher among men than women the authors, from Tufts University School of of patients who have been treated for breast for all the 12 leading causes of death in the Medicine in Boston. “A similar phenomenon cancer concentrate on the first three to five United States, a new report shows. is seen with acute myocardial infarction, years after initial treatment and that after this Also, the incidence of most types of cancer which actually occurs more often in women follow-up visits should become less frequent is higher among men, who lose 16% more than in men, but at a later age . . . Men lose or the patient should be discharged. years of potential life before the age of 75 to approximately 2.3 times more years of The Edinburgh study has confirmed previ- cancer than women do, the study found. potential life before age 75 from coronary ous results showing that the rate of distant “Males still experience higher mortality heart disease compared to women.” relapse peaked in the first five years, but in rates than females at all stages of life from Their analysis shows that mortality from contrast it found that the incidence of loco- conception to old age,” says the report, which coronary artery disease, stroke, chronic regional relapse remained constant, at 1% to was published in the Journal of Men’s Health & obstructive pulmonary disease, flu and 1.5% a year, for at least 10 years. Gender (doi: 10.1016/j.jmhg.2007.01.010). pneumonia, diabetes, HIV, motor vehicle The study, which was based crashes, homicide, suicide, ANNUAL INCIDENCE OF BREAST CANCER on data from the US Centers “Men lose approximately trauma, liver disease, and RELAPSE* IN WOMEN IN EDINBURGH for Disease Control and Pre- 2.3 times more years of cancer are all higher in men. 4 Metastatic relapses vention publication Health, life before age 75 from Mortality from all causes is Locoregional relapses United States, 2006, found that coronary heart disease also higher. 3 the sex difference begins at compared to women” In addition, the incidence conception, when 125 boys of lung, colorectal, pharynx, 2 are conceived for every 100 girls. By birth stomach, pancreas, and bladder cancers and

1 the ratio has dropped to 105 boys to 100 girls. non-Hodgkin’s lymphoma and leukaemia By their mid-30s women begin to outnumber are also higher in men. The incidence of

0 men, and by the age of 100 years women out- cancer in all sites is 46% higher in men than 1 2 3 4 5 6 7 8 9 10 No of relapses per 100 women at risk number men by a ratio of four to one. in women. Year of follow-up Although the incidence of heart disease “These discrepancies between the health * Relapses in 1312 women treated by breast conservation surgery and followed up at two sites in Edinburgh and stroke is similar in men and women, of US men and women are striking and call Source: British Journal of Cancer men lose many more years of life to these for explanation,” says the report.

1240 BMJ | 16 June 2007 | Volume 334 NEWS

into several hospitals to perform cleaning duties and provide nursing care where they have the skills, as well as to fly helicopters. Police have been stationed outside hospitals to try to control violence and intimidation aimed at hospital workers who show up for work. The strike is technically about wages but has a large political undertone. The Congress of South African Trade Unions, although allied to the government, is implacably opposed to President Mbeki’s economic policy, which the congress says provides tax benefits to rich people while neglecting social services. Unusually, this strike has united several different unions and union federations, illustrating the deep anger and frustration among government employees at government policy, pay, and rs working conditions. Although doctors are paid through the

ibeko/Reute same system, few are on strike. Those s doctors and nurses still working, however,

Siphiwe are not dressed in white coats or uniforms, South African army troops attend to a patient at Chris Hani Baragwanath Hospital in Soweto for fear of violence and intimidation.

aid, failed to disclose that his US parents take government to brother was a main board director of GlaxoSmithKline, the parent company of one court over MMR vaccine claims of the vaccine manufacturers being sued. A spokesman for Clare Dyer bmj manufacturers over the vaccine. disorders can be caused by the Judicial Communications The first of three test cases on Mr Justice Keith ruled last the MMR vaccine, by other Office said that the possibility whether the measles, mumps, week, against the parents’ childhood vaccines containing of a conflict of interest arising and rubella (MMR) vaccine can wishes, that three scientific the mercury preservative from his brother’s position “did cause autism opened in the US reports commissioned by the thiomersal (known in the not occur” to the judge. Court of Federal Claims this manufacturers for the UK US as thimerosal), or by a Jennifer Horne-Roberts, a week, just days after the hopes of litigation may be handed over combination of thiomersal barrister whose 18 year old parents in the United Kingdom to the US Department of Health containing vaccines and MMR. autistic son was one of the for a High Court trial of their and Human Services, which The case is bound to reignite would-be claimants, said: claims were dealt a final blow. is fighting claims by 4800 the controversy that arose “Legal aid has spent £15m Last Friday at the High families of children with autism when Andrew Wakefield, a [€22m; $30m], not a penny of Court in London, Mr Justice and related disorders under gastroenterologist, called for a which came to our children. Keith disbanded a group action the national vaccine injury move to single vaccines at a press I think it’s a travesty of justice against vaccine manufacturers compensation programme. The conference in 1998 to publicise that we didn’t get a trial in this by 2000 parents who blame judge ruled that the children’s research indicating possible country.” MMR for triggering autism in details must be kept anonymous links between the measles Dr Wakefield, who faces their children. when the reports are used. virus, autism, and bowel disciplinary charges before The UK action ground to a The no fault programme is disease. the General Medical virtual halt in 2004 when the outside the tort system, but UK parents have Council, is one of 17 expert Legal Services Commission hearings are under the aegis of filed a complaint witnesses for Michelle withdrew legal aid for the the Court of Federal Claims. with the Judicial Cedillo, whose hearing group action, but a few parents In three test cases, starting Complaints Board is expected to last three soldiered on. Now the few with that of 12 year old after discovering that weeks. If she is successful remaining autistic children will Michelle Cedillo from Arizona, the High Court judge the US government pl s / have their claims withdrawn or lawyers for the parents will Nigel Davis, who s could be ordered to struck out. Only two children, put forward three theories: rejected the children’s pay more than $1m in n Stilln neither of whom has autism, that autism, autistic spectrum appeals against the r compensation, as well as

now have public funding to sue disorders, and related withdrawal of legal Satu legal costs.

BMJ | 16 June 2007 | Volume 334 1241 NEWS

in brief Hearings highlight mistakes in European medicines agency recalls antiretroviral: Nelfinavir (Viracept), used to treat HIV-1, is being recalled from sale in case of tuberculosis patient the European Union after its maker, Roche, revealed that the product had been Janice Hopkins Tanne New york Mr Speaker’s tuberculosis was detected in contaminated with a harmful substance. Two hearings last week at the US Congress January after he underwent radiography for a See www.emea.europa.eu/pdfs/general/ investigated failures in the case of Andrew rib injury. On 10 May his local health depart- direct/pr/25128307en.pdf. Speaker, the 31 year old lawyer from Atlanta ment in Fulton County, Georgia, learnt that Virgin sponsors Riders for Health: who flew to France, Greece, Italy, the Czech he had multidrug resistant tuberculosis and To mark the launch on 1 June of its daily Republic, and Canada after being told that advised him not to travel to Europe for his flights from Heathrow to Nairobi, Virgin he had drug resistant tuberculosis and should honeymoon. Atlantic has donated 31 motorbikes to not travel on commercial airlines (BMJ The department could not forbid him help the health outreach charity Riders for 2007;334:1187, 9 Jun). travelling and could act only if he violated Health in rural Kenya. See www.riders.org. Health agencies could not prevent him an order. flying, could not locate him on international Mr Speaker had planned to travel on 14 Coroner warns of needless infant deaths: Ontario’s deputy chief coroner, flights, and were slow to place him on a “no May, but on 12 May he flew on a different air- Jim Cairns, says that Canadian babies aged fly” list. The agencies were tardy in notifying line to Paris and then to Greece and Rome. under 12 months are dying needlessly the World Health Organization, European On 12 May, after he had left the United because of the increasingly popular countries, and Canada, the hearings found, States, the county health department tried to practice of letting them sleep with parents and a border agent disregarded instructions serve him with a written notice advising him or a sibling. Dr Cairns said that a study of to stop him. not to travel. 195 investigated deaths between 2004 Congressional rep- Dr Julie Gerberding, director of the Centers and 2006 showed that 21 resentatives called Mr for Disease Control and Prevention (CDC), children died in unsafe sleeping environments in Speaker “a walking bio- testified that on 18 May the Department of 2005, a rise from 16 in 2004. logical weapon” and said that if Homeland Security and the CDC began the incident had involved some- trying to locate him. However, the airline Decision making on ending one with smallpox it could have tracking system couldn’t find anyone who babies’ lives lacks consensus: been disastrous. had cancelled their original reservations and The way decisions are made in the The hearings were held by made entirely new ones. Netherlands to end the lives of severely ill the Senate Appropriations Committee’s On 22 May the agencies learnt that he had and hopelessly suffering newborn babies needs to be clarified through scientific subcommittee on labour, health and human extensively drug resistant tuberculosis. On research, says a government advisory services, education, and related agencies and 23 May Mr Speaker was contacted in Rome committee (www.ceg.nl). Despite a new by the House of Representatives’ Homeland and told to go to an Italian hospital and not reporting system introduced last year (BMJ Security Committee. to fly. 2005;331:1357), no consensus has been Mr Speaker testified by telephone from On 24 May Mr Speaker and his wife flew achieved over criteria such as the degree the National Jewish Medical and Research to Prague and then to Montreal. They drove of suffering and life expectancy. Center in Denver. He said that he had been to the United States that evening and were told he was not contagious and that no one admitted by a border guard who ignored a Children of divorced parents are more likely to be taking Ritalin: forbade him flying. computerised alert. The percentage of children taking methylphenidate (Ritalin) is almost twice as high among those whose parents are divorced than among children who NHS ends the year £500m in surplus but still faces underlying deficits continue to live with two biological Michael Day London government’s insistence on cost “It now means that the NHS is parents, a study in CMAJ has found (doi: The NHS in England has turned cutting measures had turned in a very strong position to use 10.1503/cmaj.061458). the corner on its financial things around. the extra £8bn this year on the problems, without reducing “If we had not taken decisive new drugs and better services New toolkit delivers human rights approach to health: A “Right to Health” productivity or harming care, the action then the deficit would that patients rightly expect to get toolkit has been launched by the BMA government said last week. have doubled again and would on the NHS,” she said. and the Commonwealth Medical Trust Unaudited figures indicate almost certainly have doubled David Nicholson, chief to help expose situations where public that although the NHS finished again next year,” she said. executive of the NHS, claimed funds are being used unfairly, such as the financial year 2005-6 in She added that the that services to patients had the construction of more hospitals in deficit, to the tune of £547m government had managed to continued to improve as belts large cities or the purchase of expensive (€810m; $1.1bn), it had “change the culture in a minority were tightened—despite the fact equipment that will benefit wealthy or urban populations, while rural finished 2006-7 with a surplus of NHS organisations that that hundreds of clinical posts populations or vulnerable groups are of £500m. expected, year in, year out, to were axed in the past 12 months. denied even the minimum standard of The health secretary, Patricia be bailed out” by other parts of “We have done what we said health care. See www.bma.org.uk. Hewitt, claimed that the the NHS. we would do: we’ve delivered

1242 BMJ | 16 June 2007 | Volume 334 NEWS

Government says it is consigning waiting lists to history

Michael Day London The UK government has said that an end to long waiting times for treatment in the NHS in England is finally in sight. The health minister Andy Burnham said that long delays between referral by GPs and treatment in hospital would be banished for good—with no one waiting more than 18 weeks—by December next year. New figures show that in March 2007 just

Wally Santana/ap Wally under half of all patients in England received Nurses take a much needed break during an outbreak of severe acute respiratory syndrome in Taipei in 2003 their first hospital treatment within 18 weeks of GP referral. The figures also showed, however, that New regulations aim to prevent one patient in eight was still waiting more than a year for treatment. Nevertheless, Mr Burnham insisted that international health crises the latest figures provided firm evidence of Peter Moszynski London to help monitor and control six serious infec- progress made towards the December 2008 New regulations concerning public health tious diseases—cholera, plague, yellow fever, deadline. emergencies came into force this week, revising smallpox, relapsing fever, and typhus—but He said, “When it gets there, it will be a the rules that have been in force since 1969. the last three were dropped in 1969. In the huge achievement. And many will be first The regulations were agreed at the 2005 early 1990s the resurgence of epidemics seen by their GP and then treated in hospital World Health Assembly and have a far wider such as cholera in parts of South America within 10 weeks. scope than the previous ones, including pro- and plague in India, and the emergence of “This is in my view the end of waiting. I cedures for dealing with new and re-emerging new infectious agents, such as Ebola haem- think this represents the end of the culmina- diseases and chemical or radiation events. orrhagic fever, resulted in a resolution at tion of our 10 year programme.” The revision broadens the scope of notifica- the 48th World Health Assembly in 1995 to Health unions and NHS managers gave tion to the World Health Organization—from revise the regulations. qualified support to Mr Burnham’s claims. cases of cholera, plague, and yellow fever to The new regulations require automatic Jonathan Fielden, chairman of the BMA’s “all events which may constitute public health notification to WHO of smallpox, wild polio consultants’ committee, said, “The fact that emergencies of international concern and the virus, severe acute respiratory syndrome, almost half of all patients are being treated in reporting of other serious international health and new human subtypes of avian flu. 18 weeks is encouraging and is a testament risks, irrespective of origin or source.” The International Health Regulations are available to how hard NHS doctors and other health The regulations were originally intended at www.who.int. professionals have been working.”

FINANCIAL PERFORMANCE OF PRIMARY NHS ends the year £500m in surplus but still faces underlying deficits CARE TRUSTS IN ENGLAND IN 2006-7 financial stability and improved £911m, although it is good news more upbeat. She said, “Today’s

services for patients,” he said. that this has improved from the figures show that because of Deficit of >2% Critics noted, however, that 2005-6 figure of £1.3bn. the hard work and commitment Deficit between more than a fifth of NHS trusts in “It is still concerning that more of NHS staff the vast majority of 0% and 2% England were still in the red last than a fifth of organisations NHS trusts are getting back on Break even or surplus year (down from a third in 2005- (22%) are responsible for the track financially.” 6) and that these trusts had overall gross deficit now.” However, Universities UK, accumulated a deficit of nearly And he added: “The truth is the vice chancellors’ umbrellamap of england £1bn that still had to be plugged. that turning around persistent body, claimed that the surplus Niall Dickson, chief executive and underlying deficits can take had in part been achieved by London of the healthcare think tank time and may involve significant raiding education budgets (BMJ the King’s Fund, said, “Today’s changes.” 2007;334:388-9). figures cannot disguise the fact Gill Morgan, chief executive of NHS Financial Performance that the gross financial deficit the NHS Confederation, which Quarter Four 2006-07 is

figure facing the service is represents most NHS trusts, was available at www.dh.gov.uk. Source: Department of Health

BMJ | 16 June 2007 | Volume 334 1243 NEWS

SHORT CUTS

What’s new in the other general journals Kristina Fister, associate editor, BMJ [email protected]

Exercise and physiotherapy advice combination of real exercise and real advice Lowering homocysteine doesn’t significantly improved function (effect 1.1 reduce the risk of thromboembolism help subacute low back pain only points, 0.3 to 1.8, P=0.005) when compared in the short term with a combination of sham exercise and sham HOMOCYSTEINE LOWERING TREATMENT advice. Although both interventions are widely AND VENOUS THROMBOEMBOLISM EFFECT OF EXERCISE AND used for low back pain, this is the first trial to ) ADVICE ON LOWER BACK PAIN 2.5 compare the effects of exercise and advice with Placebo 6 Homocysteine lowering treatment placebo in people with strictly defined subacute 2.0 Pain 5 low back pain. Ann Intern Med 2007;146:787-96 4 1.5

3 1.0 2 The evidence on gene mutations in

1 hereditary diffuse gastric cancer is 0.5 accumulating P=0.97 0

Probability of venous thromboembolism (% 0 10 Hereditary diffuse gastric cancer is an autosomal 0 1 2 3 4 5 6 Follow-up (years) dominant syndrome of cancer susceptibility. It Adapted from Ann Intern Med 2007;146:761-7

Function 8 is caused by germline mutations in the epithelial 6 cadherin (CDH1) gene and is characterised by Observational studies have found an association a high risk for early onset diffuse gastric cancer between raised total homocysteine concentra- 4 Exercise and advice or lobular breast cancer. The ability to detect tions in the serum and venous thromboem- Advice 2 CDH1 mutations and thereby identify the bolism. Homocysteine is thought to promote Exercise syndrome might help prevention in affected thrombosis by enhancing platelet aggregation, Neither 0 people through prophylactic gastrectomy or increasing thrombin generation, impairing fibri-

6 weeks surveillance for breast cancer. It is still a chal- nolysis, and causing endothelial dysfunction. Baseline 3 months 12 months lenge, however, to tell whether a change in a A placebo controlled trial carried out in 145 Adapted from Ann Intern Med 2007;146:787-96 gene sequence is a benign polymorphism or a centres in 13 countries enrolled more than 5500 A four arm multicentre trial recruited 259 pathogenic mutation. people who were over 55 years, had cardiovas- people with subacute low back pain. The A study published last week, authored by an cular disease or diabetes mellitus, and had at duration of symptoms at baseline was more than international group of researchers, reported the least one other risk factor for atherosclerosis. six weeks but less than three months. Patients clinical and genetic findings in 38 families with Patients were randomised to a daily supplement

were randomised to receive a combination hereditary diffuse gastric cancer. In 26 families, of 2.5 mg of folic acid, 50 mg of vitamin B6,

of 12 real or sham exercise sessions with a at least two people were diagnosed with diffuse and 1 mg of vitamin B12 or placebo and were physiotherapist and three real or sham advice gastric cancer, and one case was in a person followed up for five years. sessions over six weeks. younger than 50 years. Other included families As expected, the intervention decreased total Compared with the sham interventions, real had either one family member diagnosed with plasma homocysteine concentrations, but this exercise and real advice separately reduced diffuse gastric cancer before 35 years of age, or wasn’t coupled with a change in the risk for pain (advice: −7 points, 95% CI −1.2 to −0.2, several people diagnosed after 50 years. symptomatic deep venous thrombosis or pul- P=0.011; exercise: −0.8 points, −1.3 to −0.3, The researchers were able to detect 13 monary embolism. In the intervention group, P=0.004) and improved global perceived mutations in 15 of the 38 families, which is in the mean plasma homocysteine value decreased effect (advice: 0.8 points, 0.3 to 1.2, P<0.001; accordance with the data on test sensitivity from by 2.2 µmol/l, while it increased by 0.80 µmol/l exercise: 0.5 points, 0.1 to 1.0; P=0.017) in previous reports. It seems that either we haven’t in the group randomised to placebo. Nonethe- people with subacute low back pain, but only at discovered all of the genes that contribute to less, compared with the group that received pla- six weeks. Compared with sham exercise and this disease, or some mutations are too difficult cebo, people who received the vitamins had a sham advice, a combination of real exercise and to identify at the moment. Still, more than a hazard ratio of 1.01 (95% CI 0.66 to 1.53) for real advice also improved these outcomes at six half of the mutations found in the study were venous thromboembolism, 1.04 (0.63 to 1.72) weeks (pain: −1.5 points, −2.2 to-0.7, P=0.001; recurrent, compared with only 10% reported in for deep venous thrombosis, and 1.14 (0.57 to global perceived effect: 1.3 points, 0.7 to 1.9, previous studies. 2.28) for pulmonary embolism. P<0.001), in addition to function (effect 1.1 Using haplotype analysis, the researchers Thus, decreasing homocysteine concentra- points, 0.3 to 1.9, P=0.006). were also able to demonstrate that some of the tions with folic acid and B vitamins did not However, all the effects were smaller at mutations were independent in their origin, reduce the risk of symptomatic venous throm- three months, and most were non-significant while others were due to common ancestry. boembolism in these patients. Because the lack at 12 months of follow-up. At 12 months, the JAMA 2007;297:2360-72 of efficacy of this treatment was independent

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of plasma concentrations of homocysteine third of people who received it, but it did not or creatinine clearance had declined by 50% in this trial’s population, measuring plasma improve overall survival. However, when this or more) in 27% of patients randomised to homocysteine in older adults with throm- trial was added to a previous meta-analysis, the eprodisate, compared with 40% of those who boembolism may not be justified. It may still results suggested a 12% survival benefit com- received placebo. The difference, however, did make sense in children and young adults with pared with surgery alone, which is equivalent not reach statistical significance (P=0.06). Fur- venous thromboembolism or arterial throm- to a 5% improvement in survival at five years thermore, the decline in creatinine clearance bosis, the authors say. of follow-up. Postoperative complications were was 10.9 ml per minute per 1.73 m2 of body Ann Intern Med 2007;146:761-7 not increased in the chemotherapy group, and surface area in patients randomised to eprodi- quality of life did not seem to be impaired. sate, compared with 15.6 m2 of body surface The biggest problems with postoperative area in those randomised to placebo (P=0.02). Preoperative chemotherapy improves chemotherapy had been low tolerance and low Eprodisate had no effect on progression to end outcomes in non-small cell lung compliance. However, the authors of a linked stage kidney disease or the risk of death (hazard carcinoma editorial (doi: 10.1016/S0140-6736(07)60715- ratio 0.54, P=0.20). 6) say that more than 80% of patients in their Almost all participants in the trial had at least EFFECT OF TREATMENT ON centre complete the four cycles of postopera- one adverse event, and more than a third had at QUALITY OF LIFE MEASURES tive chemotherapy that is now standard prac- least one serious adverse event. The incidence Role functioning: physical tice. They think that although preoperative of adverse events was similar in the two study 80 Surgery chemotherapy may have potential benefit, groups. Chemotherapy plus surgery surgery should not be delayed, and they are The authors conclude that eprodisate delays 60 not convinced that the current trial, although the progression of renal disease associated with important, calls for a change in this practice. amyloid A amyloidosis, and they suggest that 40 Lancet 2007 doi: 10.1016/S0140-6736(07)60714- this drug might be useful in other types of amy-

Mean standardised score 4, doi: 10.1016/S0140-6736(07)60715-6 loidosis, including familial amyloidosis and 20 Alzheimer’s disease. N Engl J Med 2007;356:2349-60 0 Eprodisate slows kidney decline in amyloid A amyloidosis Physical functioning 80 Anti-CCP antibodies are more specific EFFECT OF EPRODISATE ON EVENT than rheumatoid factor for diagnosing FREE SURVIVAL IN AMYLOIDOSIS 60 rheumatoid arthritis All patients 1.0 Serum concentrations of antibodies against 40 0.8 cyclic citrullinated peptide (anti-CCP) seem Mean standardised score to be just as sensitive and more specific than 20 0.6 rheumatoid factor for diagnosing rheumatoid tion without event Eprodisate Placebo arthritis and predicting its progression. 0 opor 0.4 0 6 12 24 36 Pr A systematic review and meta-analysis

Time from randomisation (months) 0.2 included 37 studies that looked at the diagnos-

Adapted from Lancet 2007 doi: 10.1016/S0140-6736(07)60714-4 P=0.02 tic accuracy of anti-cyclic citrullinated peptide 0 0 4 8 12 16 20 24 28 antibodies and 50 studies that assessed the diag- Surgery is the most effective treatment modality nostic accuracy of rheumatoid factor. While the Months for resectable non-small cell lung carcinoma, Adapted from N Engl J Med 2007;356:2349-60 sensitivities were 67% (95% CI 62% to 72%) and but overall five year survival rates remain low. 69% (65% to 73%) for anti-cyclic citrullinated For decades trials failed to provide evidence that Amyloid A amyloidosis is a rare complication peptide antibodies and IgM rheumatoid fac- adjuvant chemotherapy has added value over of chronic inflammatory diseases and chronic tor, respectively, the specificity for anti-cyclic surgery alone. In recent years, postoperative infections. In this condition, a proteolytic frag- citrullinated peptide antibodies was 95% (94% cisplatin and vinorelbine showed a sustained ment of serum amyloid A protein—an acute to 97%), compared with 85% (82% to 88%) for survival benefit of up to 15%, and some centres phase reactant produced in the liver—is depos- IgM rheumatoid factor. now use such platinum based chemotherapy ited extracellularly in the tissues as insoluble Early diagnosis and treatment of rheumatoid regimens as standard practice. fibrils. Such deposition causes progressive dys- arthritis are crucial to avoid irreversible damage The recent multicentre trial of preoperative function of organs and, eventually, death. A to the joints. Because rheumatoid factor can be adjuvant chemotherapy was designed and new drug, eprodisate, inhibits polymerisation present in the plasma of healthy people and started before this evidence was available. The of amyloid fibrils and their deposition in tissues, people with autoimmune diseases other than trial randomised more than 500 people with and it seems to slow down the decline in kidney rheumatoid arthritis, using anti-cyclic citrulli- non-small cell lung carcinoma (61% with clinical function seen in people who have nephropathy nated peptide antibodies can be of great help in stage I, 31% with stage II, and 7% with stage III) associated with amyloid A amyloidosis. making the diagnosis. The authors propose that to receive surgery alone or surgery combined A recent multicentre randomised trial that these antibodies should be officially recognised with three cycles of platinum based chemother- included 183 people with amyloid A amyloido- as a diagnostic marker, but also acknowledge apy administered preoperatively. Chemother- sis compared eprodisate with placebo. After that publication bias may have played a role in apy proved to be feasible, had a good response two years, disease had worsened (concentra- the favourable results. rate, and resulted in downstaging of almost a tions of serum creatinine had at least doubled Ann Intern Med 2007;146:797-808

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European education ministers have big changes in mind for higher education. Their vision sees students moving between THE Europe’s universities, taking courses that all count towards comparable qualifications, and, as a result, finding it easier to move around as employees. Governments hope COURSE that promoting this agenda will make their universities more attractive around the world and deliver a supply of high quality graduates to the workplace. They signed up to the idea with a declara- LEFT tion in Bologna in 1999.1 Since then, despite a low profile in some countries, the wheels of the Bologna process have been turning steadily, bringing closer the goal of a common OUT European higher education area by 2010. Medicine, however, seems to have been left behind. It is not that medical educators disagree with the Bologna process’s main IN THE points, and indeed it would be hard to argue that more exchange within European institutions, more comparable qualifications, and overall higher standards would be a bad thing. COLD The most obvious problem is that in the Bologna model, harmonisation of the course of study across Europe has meant countries Fitting to the model Education ministers hope adapting their curriculums to fit a two cycle The two cycle model is meant to make it that students and staff will be model, with a three year bachelors degree easier for students to move after their bach- and a two or three year masters. Ministers elors degree either to the job market or to able to move freely between agreed to this from the outset, and have further study in another geographical or reaffirmed it since then, even though it has subject area. Those who want to continue European universities by 2010. required considerable upheaval in the many up to masters level in their original subject But medicine is being left countries where longer study culminating in can do so, but students who do not are no a masters level degree has been the norm. By longer forced to carry on or miss out com- behind, as Toby Reynolds the time education ministers met in London pletely. But this fails to recognise inherent explains in May this year, most declaration signatories differences between the study of medicine were well on the way to making the neces- and that of most other subjects, medical sary changes. educators say.

MEDINE The Thematic Network on Medical Education in Europe (MEDINE) (www.bris.ac.uk/medine/) aims to address educational, institutional, and quality issues in European medical education within the framework of existing European initiatives such as the Bologna process and the European Credit Transfer System. Task forces work on five main activities: • Agreeing core competencies/learning outcomes for medical education in Europe • Developing a framework for international recognition of qualifications • Developing quality assurance standards for the process of medical education for application in Europe • Enhancing the transparency and public understanding of medical education • Exploring and developing links between medical education and research. MEDINE is supported by the European Commission and has more than 100 universities and organisations as partners.

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Bologna process The Bologna process began officially in 1999 when education ministers from 29 European countries signed the Bologna Declaration, pledging to adopt a system of comparable degrees, based on undergraduate and graduate cycles. They also promised to take steps to increase mobility of students, teachers, and researchers, including the adoption of a system of transferable credits, and to promote European cooperation on issues such as quality assurance and curriculum development. Subsequent meetings have added the doctoral level as a third stage on top of the bachelors and masters degrees, and have called for the implementation of national qualification frameworks, among other objectives. The ultimate aim is to establish a European higher education area by 2010. The process has been largely driven by higher education leaders, rather than by the European Commission, and remains a voluntary inter-governmental initiative. By the end of May 2007, 46 countries were signatories to the declaration.

“The aim would be that you would and even the basic sciences. The trouble is be harmful to this process if we were not have people entering into a bachelors pro- that it doesn’t actually lend itself to lots of allowed to plan the medical curriculum as gramme and at the end of the three years medical curricula.” a one tier system.” they would have amassed a certain number That is largely because medical educa- In addition, medical schools might take of credit points. They would then be able to tion in most European countries has moved on more bachelors candidates than they take their credits and go off to do the next away from the division between preclinical intended to allow on to the masters pro- two years, the masters, and clinical study that gramme. As the world federation points in another European “The trouble is that could have easily fitted out, it is not clear what other employment institution,” says Gareth [the basic concept of into a two cycle course. or course of study would be suitable for Williams, dean of the The curriculum is now bachelor students who did not go on to faculty of medicine and Bologna] doesn’t actually more integrated, with finish medical studies. And even if courses dentistry at the Univer- lend itself to lots of clinical and communi- were split into two, different national qual- sity of Bristol. Professor medical curricula ” cation skills and contact ity assurance and certification criteria and Williams is also coor- with patients introduced language barriers would probably make dinator of MEDINE, a network set up to early in the course. mobility between different countries’ medi- look at how European initiatives such as the “Most medical schools are now striving cal education systems difficult. Bologna process can be best applied to towards complete integration of the basic Notwithstanding these objections, several medical education, although he stresses he sciences and the clinical sciences,” says countries are adapting their medical edu- does not speak for the group: Hans Karle, president of the World Fed- cation systems to fit the Bologna model. “It was felt that within Europe there eration for Medical Education. “This will Switzerland has switched to a two cycle wasn’t enough exchange of ideas and be a problem with this two cycle system, system, with theoretical mobility between exchange of people, exchange of students. because then you will immediately try to its medical schools after the bachelor stage. Bologna was also seen as a way of raising separate the two parts into the basic sciences Denmark has introduced a bachelors degree the standards in areas of Europe that are followed by the clinical sciences. for all medical students after three years of bad, by exposing them to best practice else- “Of course that was actually the tradi- study, although its curriculum is still inte- where and by raising students’ expectations. tional way of teaching in the past. In all grated and no-one is expected to leave at The basic concept is actually quite a good parts of the world we are trying to intro- that point. And Spain, France, Austria, one, and it is applicable to lots of humanities duce this integration, and I think it would Belgium, and the Netherlands have also

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considered ways to introduce the two cycle an aid to integration for “What really matters is what is needed is to have system. those schools that cur- approved standards and Concerned by the implications of this rently just teach science that all medical degrees let medical schools work trend, the world federation called in 2005 for three years.” in Europe are regarded as with these standards in for medical schools to be able to opt out of The issue of learning the same under European their reform process, the two cycle system.2 But higher education outcomes touches on and then we could also ministers at the London meeting in May did an important role for employment law when use these standards in not mention this point.3 “It doesn’t appear the Bologna model in they patently are not” national accreditation anywhere in the ministerial communiqué. It improving medical edu- systems.” appears that it is a subject that wasn’t cov- cation. Professor Cumming leads a group Many of the changes that will take place ered,” says David Gordon, president of the in the MEDINE network looking at learn- under the Bologna model were on the cards Association of Medical Schools in Europe. ing outcomes, using a process called tuning. for European higher education anyway, Dr Since the Bologna model does not carry Tuning was initiated by a group of Euro- Karle says, especially items like transferable the enforceable weight of an international pean universities in 2000 to identify com- credits, enhanced mobility, and promotion treaty, the realisation of its aims is down to mon points of reference for generic and of lifelong learning. In addition, he adds, the legislative will of signatory governments. subject specific competencies. medical education has been slowly moving As such, UK medical schools are unlikely to “A lot of the role of Bologna is to tidy towards greater harmonisation in Europe be forced to use the two cycle model, Pro- things up,” he says. “What medical degrees since the introduction of European Union fessor Gordon says. “I don’t think it could are called across Europe, how much study directives recognising professional qualifica- creep up on us and happen without warn- is involved, what kind of degree they are, tions in 1975. ing. I think there is enough understanding whether or not they entitle the graduate to The Bologna model may just help that that things have to be done sensibly.” practise medicine. If you look across Europe along, or it may prove a catalyst for more there is no uniformity of practice, and in a radical change, but coming from within the Better standards situation where we are supposed to treat universities, not imposed from outside. Some argue, however, that the Bologna all European medical graduates equally “What really matters is that all medical process represents an opportunity for for job applications, that to me is totally degrees in Europe are regarded as the reform. “At a minimal level Bologna could unacceptable. same under European employment law mean that we simply award a bachelor of “That’s why we think our tuning project is when they patently are not,” said Professor medicine degree to all of our students after quite important. We are starting to say these Cumming. three years of medical school, which in a are areas of the curriculum that at least you “It will take a long time to alter that situ- sense wouldn’t change anything, it would mustn’t have forgotten about completely. ation, but at least some sort of start ought almost be a ghost degree,” says Allan Cum- We are not being hugely prescriptive about to be made in my view. In order to make a ming, director�� of exactly what the start there has to be an acceptance that actu- u n d e r g r a d u a t e European Credit Transfer System (ECTS) competencies or ally there is a European dimension to medi- learning and teach- The system was developed initially to allow learning outcomes cal education, that it is not just a national ing at the Univer- students to count periods of study at other should be but at issue or an institutional issue. That is what sity of Edinburgh’s�� institutions towards degrees from their own least here are the a lot of people take issue with, they say it medical school. universities. Credits are awarded in proportion to big headings that has nothing to do with Europe.” “ I f y o u t a k e workload. A full year’s study (1500-1800 hours) you have got to medical students equates to 60 credits. Credits relate only to the have.” Toby Reynolds is a medical student and former who have been at work involved, and universities accept them for Dr Karle, who Reuters journalist, St George’s, University of London, transfer on a voluntary basis. Medical educators, London SW17 0RE university for five among others, have called for the credit system to leads a MEDINE or six years, they include descriptors of a course’s content and level group looking at [email protected] deserve something alongside the amount of work required. quality assurance Competing interests: None declared. way beyond an standards, points 1 European Ministers of Education. Bologna declaration ordinary bachelors degree, so I see it as out that the Bologna model is not about of 19 June 1999. www.bologna-bergen2005. desirable from that point of view.” standardisation, rather about harmonisation no/Docs/00-Main_doc/990719BOLOGNA_ But he adds that such a change could and compatibility. DECLARATION.PDF. 2 World Federation for Medical Education, Association for also be an opportunity to modernise cur- “People might get the feeling that the Medical Education in Europe. Statement on the Bologna riculums and particularly to start looking Bologna process is heading towards a process and medical education. www.bologna- bergen2005.no/Docs/03-Pos_pap-05/050221- at what a student should have learnt on a common system of quality assurance, for WFME-AMEE.pdf. course. “I think that if you have an appro- instance a common European accredita- 3 Towards the European higher education area: priate set of learning outcomes for bachelor tion system of medical schools and their responding to challenges in a globalised world. London Communiqué, 18 May 2007. www. of medicine, which are clinical enough and programmes. I don’t think this is feasible in dfes.gov.uk/bologna/uploads/documents/ medical enough, then it could actually be a foreseeable time,” he says. “We think that LondonCommuniquefinalwithLondonlogo.pdf.

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MEDIA WATCH Ben Goldacre Why don’t journalists mention the data? Have stories about “electrosensitivity” simply been lifted from those promoting this new diagnosis?

Sometimes, as a doctor who also their symptoms over time, without unpublished. We don’t know the writes in the newspapers, a dark knowing if the phone is on or off. protocol, or whether 2/3 for one thought comes across me: wouldn’t it There have now been 37 such subject would be statistically be so refreshing—secretly, wouldn’t double blind “provocation studies” significant (there may be only three it feel so free—to leave the medical published in the peer reviewed exposures in total, for example). We thing behind, and just make stuff up, academic literature, and they are don’t know the results of the other say what I want, spin any story that almost all negative, although you subjects. But most crucially, there is pleases me, or any story that sells, and could argue that the evidence is no mention that this single selected gaily ignore the evidence? unanimous. There are, to be clear, subject in a single unpublished study For two years now the British seven studies that did find some produced a result that seems to news media has been promoting statistically significant effect for conflict with a literature of 37 studies the existence of a new medical electromagnetic signals: but for two of that have been completed, published, condition, called electrosensitivity, those, even the original authors have and are overall negative. If this whole or electromagnetic hypersensitivity. been unable to replicate the results; The lobbyists Essex study was positive, while it The story—or in medical terms for the next three, the results seem “viciously attack might make an interesting small the hypothesis—is that a wide to be statistical artefacts (one tailed anyone who splash next to the other 37, it would range of symptoms are caused by t-tests—presumptuous, you might even dares to need to be replicated and considered acute exposure to electromagnetic say—and problems with multiple mention the data, in the context of the negative signals, and that these symptoms comparisons); and for the final two, accusing them of findings. The alternative is chaos, are ameliorated by this signal being the positive results are mutually and being blown in the wind by every removed. inconsistent (one shows worsened insensitivity, of Type I error. The features have a lot in common mood with provocation, and the other attacking sufferers, So why doesn’t the media ever with what might often conventionally shows improved mood: still sure a one and of denying mention this data? Perhaps they be called “medically unexplained tailed t-test is reasonable?). the reality of their deliberately and mischievously leave symptoms”: tiredness, difficulty These studies test the very symptoms it out. Perhaps they never came across concentrating, headaches, nausea, hypothesis reported on repeatedly it, and are incompetent. Or perhaps bowel complaints, aches in the limbs, in the media: symptoms are brought they simply lifted their stories verbatim crawling sensations or pain in the skin, on by exposure to a source of from aggressive and well coordinated and more, for which no explanation is electromagnetic signals, and cease lobbyists who promote this new found. Such symptoms have existed when the source is removed. And ” diagnosis (some of whom also sell since long before the appearance of not only are the studies ignored, but expensive equipment to sufferers, “electrosensitivity,” and the absence sometimes it feels like the media are such as insulating paint at £50 a litre, of a clear cause is extremely troubling actively teasing us. A recent Panorama and insulating beekeeper hats for trips to both patients and doctors. documentary on BBC 1 covered the outdoors). If these symptoms were caused by possible dangers of Wi-Fi computer Not only do these lobbyists electromagnetic signals, then it should networks, and what little evidence the observe a monastic silence on the prove possible to study that, ideally in programme did present was flawed in issue of the provocation studies, but double blind conditions: and yet the a number of ways. they also viciously attack anyone media coverage invariably focuses A large chunk of the programme who even dares to mention the data, on the scandal of how research into was devoted to electrosensitivity. It accusing them of insensitivity, of this area has been neglected. But covered the question of testing the attacking sufferers, and of denying the research has been done. In fact, phenomenon, in a double blind study. the reality of their symptoms. dozens of double blind studies have The programme makers even followed Symptoms, of course, stand as been performed, but they have been someone into a lab at Essex University real, regardless of their cause; and systematically ignored by almost every where they had participated in one if you were going to offer guilt trips single journalist covering the issue. provocation study. We are told that around, you could fairly argue that A typical experiment would involve this subject did correctly identify when those who obfuscate on the causes a mobile phone, hidden in a bag the signal was present or absent two are themselves hindering better for example, and each subject— thirds of the time, to a visual backdrop understanding and treatment, and so chosen from people who report of sciencey looking equipment. harming patients. that their symptoms are caused by But this was anecdote dressed Ben Goldacre is a doctor and writer, electromagnetic signals—recording up as data. The study is currently London [email protected]

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Medicine and the media Don’t blame it all on the bogey UK and European policymakers and journalists could learn a lot from the way in which their US counterparts are ready to turn the heat on drug regulators, not just on big pharma, writes Michael Day

The newspapers love a bogeyman. And big by Marxists in order to undermine the oil the heat to be turned up on the people who pharma fits the bill perfectly. The image of industry. If, however, you tried to move the regulate drug companies, rather than simply obscenely well paid executives ripping off the argument on a little from “drugs companies demonising these profit-making organisations NHS and poisoning the masses for the sake are evil” to “the regulators are to blame,” news for cutting corners and doing what they do of quick profits has united newspapers of all editors’ eyes would glaze over. best . . . making profits. political persuasions in a deep-held suspicion The British press has been quick to report No so in the United States, where thorough of the companies’ method and motives. concerns about “disease mongering” by the newspaper reporting of the Food and Drug During my stint as the Sunday Telegraph’s drugs industry as well as safety fears over Administration’s inadequacies has prompted health correspondent, under the impeccably Vioxx (rofecoxib), Seroxat (paroxetine), members of the US Congress to now push right-wing and laissez-fare reign of Dominic Avandia (rosiglitazone), and others. But it for proper post-marketing surveillance of new Lawson, bashing drugs companies always has largely been left to campaigners such as medicines, and even for the FDA to be split guaranteed you space in the paper. And bear Charles Medawar in Social Audit to tackle into two separate bodies—one that awards in mind this was a publication that consid- the failings of the Medicines and Healthcare drugs licences, and another that continues to ered global warming something invented products Regulatory Agency—and to call for monitor safety and has the power to rescind them. The real impetus behind these calls for change has been the Vioxx disaster. The agency’s failure to act more quickly on Vioxx, and the It’s when the film focuses behaviour of key figures within on the FDA’s role in the the organisation are probably Vioxx affair that things the most alarming aspects of a get really interesting new investigative documentary on the dark side of the pharmaceutical industry, We’ll Take Care of You by Lat- tanzio Firmian and Alberto Baudo. The film makers begin with some predict- able attacks on big pharma. Drugs company executives are portrayed as Wild West vil- lains and predatory animals. Victims of drug side-effects are nice, ordinary Joes who were just fine until they started taking the tablets— though it’s worth recapping the extent of the Vioxx scandal. Merck’s own paper in the New England Journal of Medicine in June 2000 found that the drug increased users’ risk of stroke or heart attack by four to five times. But despite this risk being in the public domain in June 2000, Merck continued to promote and sell the osteoarthritis treatment until its withdrawal in September 2004. By this time an estimated 60 000 people who had been prescribed the drug in the US alone had died from stroke or heart attack. But it’s when the film focuses on the FDA’s role in the affair that things get really interesting. Despite the publication in June 2000 of the pivotal NEJM paper highlighting the cardiovascular risk posed by Vioxx, the FDA took no action. In September 2001, the FDA said in a

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letter to Merck that the company’s assertion that Vioxx was safe for the heart was “simply incomprehensible.” Still it took no action. The following year, the warning label on the Vioxx packets was finally changed to alert patients to cardiovascular risks. Seen squirming under questioning by Con- gressional investigators in the documentary, Steven Galson, the director of the FDA’s Center for Drug Evaluation and Research, agreed that even this modest label had taken “longer than it should have.” And his explanation for the delay? “We were trying to work out exactly what was acceptable to both sides.” Yes, you read that correctly. The issue of a mass-market medicine for a non life-threatening disease raising the risk of heart attack by 500% in millions of people was not a public health emergency in the FDA’s eyes, but simply a source of 18 months’ polite negotia- WHATS ON THE WEB tion—with the protection of the manufactur- What’s so precious about originality? er’s commercial interests evidently high on Research aside, the efforts contributors to medical and science the agenda. Almost as bad, the documentary showed journals are forced to go to to avoid self plagiarism are just a waste of how one of the chief whistleblowers at the time, writes Simon Chapman FDA, David Graham of the FDA’s Office of The ethics of banning smoking outdoors original research I well understand the Drug Safety, needed Congressional protection (I am opposed) is something that I have point, but many editors on this list are in order to keep his job after threats and abuse written on several times, most recently editing journals whose standard fare culminated in his sacking from the agency. at length in a forthcoming book (Public goes beyond original data into policy Galson has retained his job of head of the Health Advocacy and Tobacco Control: analysis and contributions designed to Office of New Drugs at the FDA. The FDA’s Making Smoking History. Oxford: leverage change in some of the world’s Commissioner, Lester Crawford, who also Blackwell, 2007). most pressing problems (climate came under fire for his role in the Vioxx scan- This issue has got up some worrying change, violence, poverty, obesity, etc). dal, quit the agency and has since taken up a momentum lately and so I find myself Anyone who thinks that only data, rather job lobbying on behalf of the pharmaceutical being asked to increasingly speak than interpretation and commentary, industry. and write about it. I tell those asking change the world should get off at the Cynics would say this is why FDA execu- me that I have little more to add than next stop. tives make life easy for big pharma—they’re I have already written in my previous Ought we not to differentiate thinking of a cushy six-figure salary there in contributions, yet they insist they want between original data and analysis/ the not too distance future. yet another, “different” piece. What is commentary? Do we really believe Some of the campaigning elements of the the point, precisely, in me spending that humanity is best served by the US Congress have the bit between their teeth hours manicuring, paraphrasing, and straitjacket of requiring debates, now—one of the key movers, Democrat Henry in every other way trying to express the policy advocacy and commentary to Waxman, is leading the attack on the FDA same basic arguments that I originally always be wholly original? Do we really over its handling of rosiglitazone, the GSK felt I expressed as well as I could? All believe that significant contributors to diabetes treatment that is also under suspicion in the name of not “self plagiarising.” these debates really only deserve one for raising patients’ heart attack risk. I can play around with trying to top, bite at expressing their best And there’s little sign of the press relenting. tail, and middle things differently, but shots, and if the rest of the world It would appear that even Washington DC’s if the core of what I’m wanting to say is happens to miss out on their original mighty pharmaceutical lobbying machine will essentially the same, and I’m running contribution in “Calathumpian Journal have its work cut out to prevent some major into agendas about originality, what is of Significant Issues,” this is just too changes to drug regulation. more important here? bad . . . all in the name of preserving Given the depressing similarities between Media outlets all over the world daily publishing integrity? US and European drug regulation—the reli- buy exemplary articles, syndicated Simon Chapman is professor of public ance on industry funding, the dearth of post- columns, features, etc, in recognition health, School of Public Health, marketing surveillance, etc—perhaps it’s time that their readerships will not have read University of Sydney for our policymakers and journalists to start a piece that was originally published [email protected] asking a few more questions this side of the elsewhere, the web notwithstanding. This is an edited version of an article that Pond. Why do we in the health and medical appeared on the listserv of the World Michael Day is a freelance journalist, London specialist journal media feel so precious Association of Medical Editorson 30 May 2007 [email protected] about originality? When it comes to

BMJ | 16 june 2007 | Volume 334 1251 head to head head to head

Should folic acid fortification be mandatory?

Nicholas J Wald, director, Wolfson Institute of Preventive Medicine, A meta-analysis of seven cohort and nine case- progressed while the macrocytic anaemia Barts and The London, Queen Mary’s School of Medicine and control studies of colorectal cancer found an (indistinguishable from that due to folate Dentistry, University of London, London EC1M 6BQ, 8 [email protected] Godfrey P Oakley, professor, Department overall reduction in risk with folic acid intake. deficiency) improved because high dose folic of Epidemiology, Rollins School of Public Health, Emory University, Smaller cohort studies have been cited to show acid can reverse the arrest of DNA synthesis Atlanta, GA 30322, USA that low folate may protect against colorectal that causes a B-12 macrocytosis deficiency. Delay in fortifying flour with cancer,9 but this interpretation arises from a The doses of folic acid used in fortification folic acid is unjustified. In data subset analysis, is probably due to chance, are below those which resolve the anaemia Yesmany countries this public and is unsupported by the overall results of the associated with B-12 deficiency.15 Moreover, health measure has increased blood folate trial. these concerns are unwarranted, because the levels and reduced neural tube defects. When The aspirin-folate prevention trial con- clinical consequences of B-12 deficiency can the effect of folic acid on neural tube defects cluded that folic acid did not result in a sig- be avoided by awareness of the neurological was shown in 1991, prevention was attempted nificant decrease in large bowel adenomas,10 nature of B-12 deficiency , the application of through diet and supplements.1 But supple- but absence of benefit is not equivalent to the the appropriate biochemical tests, and treatments must be taken before pregnancy is presence of harm. An observed increase of bor- ment with B-12. confirmed, and most pregnancies remain derline significance was not considered a real Synthetic folic acid is ideal for fortification: unprotected. effect. Random differences between groups are it is more bio-available than natural folate and, Voluntary fortification has proved inad- common in small trials; for example, there were unlike natural folate, is stable in food, even equate. Expert advisory committees consider- half the number of deaths from all causes in during cooking. It is readily absorbed into the ing mandatory fortification with folic acid have the folic acid group compared with the control bloodstream—an advantage, as folic acid must concluded that it is necessary, effective, and group in this trial, which does not mean that pass from the mother’s blood to the fetus to be safe; about 40 countries, including the United folic acid protects against all deaths. A meta- effective. Millions of people have consumed States, have adopted this policy. analysis showing a relative risk of 0.99 (0.98 folic acid as supplements for decades before It is important to reach people who are less to 1.01) for breast cancer and folate indicates fortification and as a result have had free folic well off—they have most to gain from fortifica- that folic acid neither increases nor decreases acid in their blood with no credible evidence tion. In Chile, where fortification has achieved the risk of breast cancer.11 It is important not of any adverse health effects. a relatively high folic acid intake, neural tube to overinterpret marginally significant associa- defects were reduced by 43%; in tions from individual studies (such Overall assessment the United States, with a lower Supplements must as one on breast cancer12); such Folic acid fortification shows clear benefit in fortification level, the reduction be taken before associations can arise by chance, preventing spina bifida and anencephaly, with was about 20%.2 With fortifica- pregnancy is confounding, or both. The evi- substantial evidence on safety, and no valid tion on a global basis, each year confirmed dence on folic acid and cancer is indication of harm. Public health authorities about 250 000 children could be that there is no harm, and there have a responsibility to take action, recognising saved from spina bifida or anencephaly and the may be a long term benefit on colorectal that failure to fortify has serious health conse- devastating consequences.3 This public health cancer. quences; withholding a benefit causes harm. opportunity should not be lost. The case for fortification is sufficiently made Competing interests: GPO is a co-inventor (while at CDC, Evidence indicates other benefits from folic on preventing neural tube defects, irrespective compensation, if any, will be under the regulations of CDC) of a acid fortification: a modest but important pro- of cardiovascular disease prevention. Until patent that covers adding folic acid to contraceptive pills and has been a paid consultant to Ortho McNeil on the matter of folate. tection against cardiovascular disease and a sug- recently, the randomised trials of folic acid NJW is a co-inventor of a combination pill for the prevention of gested reduction in the evidence of a cleft lip and cardiovascular disease lacked the statisti- cardiovascular disease, which optionally may include folic acid. and in the rate of cognitive decline with age.4-6 cal power to show that lowering homocysteine References are in the full version on bmj.com We consider the scientific validity of four con- by folic acid has a preventive effect, though the cerns that are raised against fortification. HOPE-2 study showed a significant reduction in strokes.13 A meta-analysis has now confirmed Link with cancer this.14 The genetic polymorphism studies also If judgment were to be made, it would be that indicate that homocysteine is a cause of cardio- folic acid prevented cancer, not that it caused vascular disease.4 it. The US nurses’ health study followed 88 756 The assertion that folic acid exacerbates women prospectively, and indicated that long B-12 deficiency is without scientific foundation. term use of folic acid may substantially reduce It is based on reports published more than 50 the risk of colon cancer.7 After 15 years, the years ago, when patients with B-12 deficiency relative risk was 0.25 (95% confidence interval had unknowingly been incorrectly treated with 0.13 to 0.51), representing 15 instead of 68 new folic acid instead of B-12, so the neurological colon cancers per 10 000 women aged 55 to 69. consequences of untreated B-12 deficiency

1252 BMJ | 16 june 2007 | Volume 334 head to head head to head

The UK’s Food Standards Agency recently recommended mandatory folic acid fortification of some foods. Nicholas Wald and Godfrey Oakley argue that it’s a safe effective way of preventing spina bifida and anencephaly—but Richard Hubner and colleagues say that more research is needed

Richard A Hubner, clinical research training fellow, questionnaires assessing folate intake has also subject was increased by folic acid supplemen- [email protected] Richard D Houlston, professor of been questioned.6 tation (rate ratio 1.44; 95% confidence interval molecular genetics, Institute of Cancer Research, Section of Cancer Genetics, Sutton SM2 5NG, Kenneth R Muir, professor of Some studies have indictated that folate 1.03 to 2.02), as was the incidence of advanced epidemiology, University of Nottingham, Division of Epidemiology from foods may have a different effect than colorectal adenoma with high malignant poten- and Public Health, Queen’s Medical Centre, Nottingham NG7 2UH folic acid from supplements. A cohort study tial (1.31; 0.90 to1.89). One explanation for this Mandatory fortification with of 25 000 postmenopausal women reported is that folic acid supplementation promoted the folic acid aims to increase folate that although folate from food was not associ- growth of pre-existing aberrant crypt foci or No intake folate in women during ated with risk of breast cancer, high total folate small adenomas and these were missed at ini- early pregnancy to reduce neural tube defects intake, mainly from folic acid supplementation, tial colonoscopy. If this effect of folic acid is in their babies. The case for mandatory fortifi- significantly increased risk by 32%.7 A meta- genuine it is a public health concern as more cation is strengthened by the purported asso- analysis of cohort studies investigating folate than 25% of people aged over 50 have asymp- ciation of increased folate intake with reduced intake and colorectal cancer risk reported a sig- tomatic colorectal adenomas.14 incidence of cancer. But new data suggest that nificant reduction in risk in people with high folate supplements may promote cancer. intake of folate from food—but the association Lowering homocysteine Folate metabolism influences several crucial was almost null when folate was from diet and Folic acid supplements combined with other pathways, including DNA synthesis and methyl‑ folic acid supplements.8 B vitamins result in lowered plasma homo- ation, abberations of which play a role in car- cysteine, and several randomised intervention cinogenesis. Altered folate metabolism may Potential cancer promoting effects studies have investigated their use in prevent- disrupt these processes, so folate deficiency and A neoplastic clone of cells has enhanced growth ing cardiovascular disease. A meta-analysis supplementation could influence cancer risk. compared to normal tissue. This attribute is of these studies showed that lowered plasma This may be further complicated by using syn- exploited by chemotherapeutic drugs, which homocysteine may not prevent ischaemic heart thetic folic acid: its effects on folate metabolism inhibit folate metabolism enzymes, interrup‑ disease (pooled rate ratio 0.96; 0.81 to 1.13).15 are not identical to natural folates.1 ting DNA synthesis and inhibiting growth of The two largest trials provided data on cancer Epidemiological studies have found that tumours. Extra folate could promote tumour incidence. Patients randomised to folic acid high folate intake is associated with a reduced growth by allowing increased DNA synthesis. supplements were 22% more likely to develop risk of cancers of the breast, lung, pancreas, Evidence that timing of folic acid supplemen- cancer in one trial,12 and 36% and 21% more oesophagus, stomach, cervix, and the colorec- tation may determine its effects on colorectal likely to develop colorectal cancer and prostate tum in particular.2 But recent studies have cast carcinogenesis comes from two genetic mouse cancer in another.13 Although these increases doubt over the epidemiological evidence. A models of colorectal cancer.9 10 In both models, were not statistically significant, cancer inci- large cohort study found an increased risk of if intervention was started before lesions devel- dence was a secondary end point for which colorectal cancer in people with high plasma oped, moderate folate deficiency enhanced the both trials were underpowered. concentrations of folate,3 and a meta-analysis development of cancer and folic acid supple- The level of exposure to folic acid from of cohort studies investigating folate intake mentation suppressed it—but once a preneo- fortification may be crucial, and the low level and breast cancer risk reported no effect.4 The plastic lesion was present, supplementation exposure associated with fortification may not inverse relation in some studies of colorectal promoted tumour growth. These result in any cancer promoting cancer and folate intake may have been con- studies have led to the hypothesis New data suggest effects. But levels of folate intake founded by dietary and lifestyle factors, and that in normal epithelial cells folate that folate after fortification are hard to pre- adjustment for these may have abolished the deficiency promotes neoplastic supplements may dict, and the increase in the US association between folate intake and colorec- transformation, which can be since fortification has been twice promote cancer tal cancer risk.5 The validity of food frequency avoided by folic acid supplemen- what was anticipated.16 tation, whereas supplementation Reducing neural tube defects is promotes the growth of existing preneoplastic a worthy aim, but further investigation of the and neoplastic tissue. Although these studies potential cancer promoting effects of exposure were in animal models of colorectal cancer, to folic acid in susceptible people is desirable randomised intervention trials in humans sup- before mandatory fortification starts. port this hypothesis.11-13 Funding: RAH has a clinical research training fellowship from The aspirin-folate polyp prevention study Cancer Research UK. recruited 1021 people who had colorectal ade- Competing interests: None declared. noma removed at colonoscopy, randomised References are in the full version on bmj.com to intervention with folic acid (1 mg/day) or spl / placebo, and it assessed polyp recurrence by WHERE DO YOU STAND ON THE ISSUE? 11 colonoscopy at three and six years. The mean Vote now on bmj.com pasieka number of recurrent colorectal adenomas per

BMJ | 16 june 2007 | Volume 334 1253 ANALYSIS

How effective are expert patient (lay led) education programmes for chronic disease? Considerable hyperbole has surrounded the UK expert patient programme, and it has received considerable funding—but will its impact meet expectations?

Chronic conditions now account for 60% of deaths Chris Griffiths and professionals could teach self care equally well. worldwide and are imposing an increasing burden professor of primary care Lorig argued that the lay led model was attractive 1 Gill Foster on society and health services. Self management pro- senior research fellow because lay educators were plentiful and relatively grammes are commonly used to help patients learn Jean Ramsay cheap and could help other people with the disease the skills to manage their own conditions better.2 The senior research fellow by “modelling” self care more effectively than healthy Sandra Eldridge NHS in the United Kingdom, and countries in Europe reader in statistics professionals. (especially Scandinavia), Australasia, and North Amer- Stephanie Taylor ica have chosen specifically to use courses tutored by senior clinical lecturer in health Self care programmes services research, Centre for trained lay leaders, rather than health professionals Health Sciences, Barts and The The success of the Stanford arthritis self management such as nurses.3 Considerable resources have been London, Queen Mary’s School of programme (http://med.stanford.edu/patienteduca- allocated to support and run such programmes. A Medicine and Dentistry, London tion/) spawned a generic programme, the chronic dis- E1 2AT major attraction for healthcare planners has been ease self management programme, which was adopted Correspondence to: C Griffiths the expectation that such courses will reduce use of [email protected] in the UK as the expert patient programme. Both con- health care and will deliver long term cost savings.4 sist of six weekly, lay tutored sessions (box) fostering More debate about the impact of lay led, self manage- self care skills through participative techniques such ment programmes is needed. This article opens up as modelling and action planning. this debate and examines the evidence that “expert These programmes are based on Bandura’s social patients” consume fewer healthcare resources, with cognitive theory of behaviour, which states that the particular reference to data from trials in the UK. key predictors of successful behaviour change are confidence (self efficacy) in the ability to carry out Involving patients in health care an action and expectation that a particular goal will Two main arguments drive the shift towards increas- be achieved (outcome expectancy).8 Self efficacy is ing patients’ involvement in health care.5 Firstly, it is seen as an early step in causal pathways of behaviour unethical for patients not to be involved in decisions change in self management programmes; increasing about their health and, by extension, for the public self efficacy (confidence) is a prerequisite for behav- not to be involved in how care is organised. Secondly, iour change which, through improved self manage- greater patient involvement in the consultation may ment, may influence health and healthcare use. Many lead to greater satisfaction, and perhaps more impor- health services around the world have adopted this lay tantly to better health. Patients’ involvement has been led model in the hope that it will deliver cost effective championed by organisations like the Picker Institute health gains. (www.pickereurope.org), which monitor patients’ experience of care and highlight deficiencies. Systematic Content of standard six week chronic disease self reviews show that interventions can promote patients’ management programme involvement and possibly greater satisfaction, but the Session 1—Course overview; acute and chronic conditions 6 jury is still out on whether this leads to better health. compared; cognitive symptom management; better Against this background, the UK government has breathing; introduction to action plans promoted the idea of a patient centred NHS, with Session 2—Feedback; dealing with anger, fear and initiatives such as patient advisory liaison services, frustration; introduction to exercise; making an action plan attempts to improve access to care, and “choose and Session 3—Feedback; distraction; muscle relaxation; book,” a system that allows patients to choose the fatigue management; monitoring exercise; making an hospital to which they are referred by their general action plan Session 4—Feedback; making an action plan; healthy practitioner. Another initiative, the expert patient eating; communication skills; problem solving programme, was first announced in Saving Lives: Our Session 5—Feedback; making an action plan; use of Healthier Nation.7 The programme is based on the medication; depression management; self talk; treatment work of Halstead Holman and Kate Lorig at Stanford decisions; guided imagery University, who developed the idea of teaching arthri- Session 6—Feedback; informing the healthcare team; tis self care by using lay tutors in 1979.8 Early, small working with your healthcare professional; looking forward. scale comparisons suggested that trained lay people

1254 BMJ | 16 JUNE 2007 | Volume 334 ANALYSIS

Randomised trials of lay led self management programmes in the UK

Outcome Generic health related Study Intervention Condition No of patients Self efficacy Psychological health quality of life Use of health care Barlow et al 200013 ASMP Arthritis 544 Improved Improved Unchanged Unchanged Griffiths et al 200515 CDSMP Various 439 Improved Unchanged Unchanged Unchanged Buszewicz et al 200612 ASMP Arthritis 812 Improved Unchanged Unchanged Unchanged Kennedy et al 200714 CDSMP Various 521 Improved Improved Improved Unchanged ASMP= arthritis self management programme, CDSMP=chronic disease self management programme.

Great expectations of four studies, and more importantly, use of health In 2001 the expert patient task force, led by the care has remained stubbornly unaltered. The latter chief medical officer, Sir Liam Donaldson, con- is a considerable disappointment because the expert cluded that lay led self management programmes patient programme has been heavily promoted by the for chronic diseases (or long term conditions) would UK Department of Health as part of a drive to reduce improve health status, slow the progression of dis- use of acute health care. ease, and reduce healthcare use, and that the NHS Several factors may explain the failure of lay led should invest heavily in the expert patient pro- programmes in the UK to reduce the use of health gramme.9 In 2003 the chief medical officer wrote care. Firstly, lay led programmes may do as much an editorial for this journal asserting that the expert to promote consultation as they do to reduce it. patient programme ushered in a new era of oppor- The chronic disease self management programme tunity for the NHS.10 He envisaged the programme teaches techniques to improve communication with reducing healthcare use and even mortality when clinicians, so patients may be encouraged to con- he said: “Such people those with confidence live sult more. Secondly, any reductions in unscheduled longer, are healthier, and are an example of how (emergency) care may be obscured by increases more assertive engagement with the health care in scheduled care. Thirdly, self management pro- system can improve both the length and the qual- grammes may not be as effective at reducing health- ity of people’s lives.” To date, the Department of care use in settings such as the UK, which have Health has invested £18m (€27m; $36m) in the universal healthcare coverage and well established programme, with an explicit goal of providing the primary care. It is unlikely that poor delivery of the course to 100 000 patients. programme in the UK is a cause since course tutors are assessed and course quality is strictly monitored. Evidence for change in use of health care Three trials of the chronic disease self management Recently, a rapid review (commissioned by the programme in the United States show inconsistent National Institute for Health and Clinical Excellence) effects on use of health care.16-18 The much cited gave a cautious welcome to lay led self management report of a 40% reduction in physician visits in the interventions but pointed out that most evaluations United States comes from a methodologically weak, were short term and set in the United States, and some retrospective comparison, in which arthritis patients of the data were uncontrolled.11 A recent paper by in the community who had volunteered for self care Buszewicz and colleagues provides the longest dura- education were compared with a group of arthritis tion of controlled follow-up to date (one year).12 Of patients with no explicit interest in self management the four evaluations in the UK, two test the arthritis who were under the care of rheumatologists.19 self management programme12 13 and two the chronic Trials examining use of health care in the UK disease self management programme, including the are unlikely to have missed an effect of this national evaluation of the expert patient programme magnitude. carried out by the National Primary Care Research Centre in Manchester.14 15 The results of these four Testing questions studies are similar (table). The good news is that these Although improvements in self efficacy and psy- programmes increase patients’ self efficacy—in essence chological health are welcome, these disappointing their confidence to change behaviour—and can lead results can be compared with the impact of other to improved psychological health (although the effect professionally led self management or rehabilita- sizes seem small). We found the chronic disease self tion interventions in the UK. The six week heart management programme improved self efficacy in manual programme uses a similar patient empower- Bangladeshi patients, suggesting that it may be useful ment model for rehabilitation after a cardiac event.20 for ethnic minorities.15 However, the changes in self Over a year, the programme improved psychologi- efficacy are generally modest and it is unclear how cal adjustment, especially in participants with high much patients value improvements in self efficacy anxiety and depression scores at baseline, and it compared with, say, a reduction in symptoms or a reduced visits to general practitioners and readmis- gain in health related quality of life. sion to hospital. Psychological interventions for dia- There are also important negative findings: generic betes improve glycaemic control.21 Exercise based measures of self rated health were unaltered in three cardiac rehabilitation reduces mortality.22 Pulmonary

BMJ | 16 JUNE 2007 | Volume 334 1255 ANALYSIS

rehabilitation programmes produce clinically Summary points 1 World Health Organization. Chronic diseases and health promotion. important reductions in breathlessness and fatigue 2007. www.who.int/chp/en/ In the United Kingdom 2 Newman S, Steed L, Mulligan K. Self-management interventions for in patients with cardiac obstructive pulmonary dis- the expert patients 23 chronic illness. Lancet 2004;364:1523-37. ease, yet fewer than 2% of these patients in the programme will be rolled 3 National Health Service. Expert patients programme. 2007. www. UK have access to pulmonary rehabilitation each out to 100 000 patients expertpatients.nhs.uk/public/default.aspx 24 4 Wanless D. Securing our future health: taking a long-term year. by 2012 view. London: HM Treasury, 2002. www.hm-treasury.gov.uk/ Why have these interventions had more impact Four randomised trials consultations_and_legislation/wanless/consult_wanless_final. than lay led programmes? Firstly, these programmes set in the UK indicate cfm that although lay led 5 Coulter A. Paternalism or partnership? BMJ 1999;319:719-20. may be better targeted towards higher risk individu- 6 Lewin SA, Skea ZC, Entwistle V, Zwarenstein M, Dick J. Interventions als, who experience greater morbidity. Secondly, programmes increase for providers to promote a patient-centred approach in clinical key features of successful self management pro- patients’ confidence to consultations. Cochrane Database Syst Rev 2001(4):CD003267. manage their disease, 7 Department of Health. Saving lives, our healthier nation. London: grammes include correcting erroneous health beliefs they are unlikely to Stationery Office, 1999. (Cm 4386.) www.archive.official- and teaching specific, clinical, disease management documents.co.uk/document/cm43/4386/4386.htm reduce either hospital 8 Bandura A. Self efficacy: toward a unifying theory of behavioral skills—for example, using a written self management admissions or the use change. Psychol Rev 1977;84:191-215. plan for asthma.25 Thirdly, cardiac and pulmonary of other healthcare 9 Secretary of State for Health. The expert patient: a new approach for rehabilitation programmes combine a structured resources in the NHS chronic disease in the 21st century. London: Stationery Office, 2001. www.dh.gov.uk/en/Publicationsandstatistics/Publications/ exercise programme with self management advice; Lay led programmes in the PublicationsPolicyAndGuidance/DH_4006801 lay led programmes in their current form do not UK need evaluation before 10 Donaldson L. Expert patients usher in a new era of opportunity for the NHS. BMJ 2003;326:1279-80. provide these additional components. they can be recommended over other programmes 11 Bury M, Newbould J, Taylor D. A rapid review of the current state of knowledge regarding lay-led self management of chronic illness. with established impact Questions about impact London: NICE, 2005. www.nice.org.uk/page.aspx?o=526636 12 Buszewicz M, Rait G, Griffin M, Nazareth I, Patel A, Atkinson A, et al. Considerable hyperbole has surrounded the UK Self management of arthritis in primary care: randomised controlled expert patient programme, and some patients trial. BMJ 2006;333:879-83. 13 Barlow JH, Turner AP, Wright CC. A randomized controlled study of attending courses have given powerful personal the arthritis self-management programme in the UK. Health Educ Res accounts of their benefits. 2000;15:665-80. However, these accounts must now be seen in the 14 Kennedy A, Reeves D, Bower P, Lee V, Middleton E, Richardson G, et al. The effectiveness and cost effectiveness of a national lay-led self context of the modest results of four well powered care support programme for patients with long-term conditions: a randomised trials in the UK. Although early results pragmatic randomised controlled trial. J Epidemiol Community Health 2007;61:254-61. suggest that the programme can improve patients’ 15 Griffiths CJ, Motlib J, Azad A, Ramsay J, Eldridge S, Khanem R, et confidence, questions remain about its impact on al. Randomised trial of a lay-led self-management programme health in patients in the UK. How important is for Bangladeshis in the UK with chronic disease. Br J Gen Pract 2005;55:837-42. self efficacy as an outcome? How long do effects 16 Lorig K, Sobel D, Stewart A. Evidence suggesting that a chronic on self efficacy or other outcomes last? Do lay led disease self-management program can improve health status while reducing hospitalization: a randomized trial. Medical Care programmes improve key measures of disease pro‑ 1999;37:5-14. cess such as glycaemic control, blood pressure, or 17 Lorig KR, Ritter PL, Gonzalez VM. Hispanic chronic disease self- weight? Should lay led programmes be targeted management: a randomized community-based outcome trial. Nurs Res 2003;52:361-9. at patients with particular illnesses, perhaps with 18 Haas M, Groupp E, Muench J, Kraemer D, Brummel S, Sharma R, et al. courses specific to these diseases, or at patients with Chronic disease self-management program for low back pain in the elderly. J Manipulative and Physiological Therapeutics 2005;28: particular psychological profiles? Could the expert 228-37. patient programme be made more effective, perhaps 19 Lorig KR, Mazonson PD, Holman HR. Evidence suggesting that health adding slots for clinicians to teach clinical disease education for self-management in patients with chronic arthritis has sustained health benefits while reducing health care costs. Arthritis management skills? Our forthcoming Cochrane Rheum 1993;36:439-46. review should throw light on some of these ques- 20 Lewin B, Robertson IH, Cay EL, Irving JB, Campbell M. Effects of 26 Contributors: CG and ST self-help post-myocardial-infarction rehabilitation on psychological tions, but more well designed trials are needed to wrote the first draft, which was adjustment and use of health services. Lancet 1992;339:1036-40. evaluate fully the contribution of lay led education commented on by all authors. CG 21 Ismail K, Winkley K, Rabe-Hesketh S. Systematic review and programmes. The government should invest in such is guarantor. meta-analysis of randomised controlled trials of psychological interventions to improve glycaemic control in patients with type 2 Funding: North East London a programme of research in the same way it has diabetes. Lancet 2004;363:1589-97. invested heavily in implementing the expert patient Consortium for Research and 22 Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N, Ebrahim S. Development (NELCRAD) programme. Exercise-based rehabilitation for coronary heart disease. Cochrane contributed to the costs of the Database Syst Rev 2001(1):CD001800. Although general practice leaders in the UK may review. GF is funded by a Health 23 Lacasse Y, Goldstein R, Lasserson TJ, Martin S. Pulmonary be tempted to include referral to the programme in Foundation Research Fellowship rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006(4):CD003793. future versions of the quality and outcomes frame- and ST is funded by a Department of Health Public Health Career 24 British Thoracic Society, British Lung Foundation. Pulmonary work, data so far suggest that this would be prema- Scientist Award. rehabilitation survey. 2003. www.lunguk.org/downloads/BLF_pul_ ture. The expert patient programme is switching rehab_survey.pdf Competing interests: All authors 25 Gibson PG, Powell H, Coughlan J, Wilson AJ, Abramson M, Haywood P, from Department of Health funding to becoming a listed are researchers in the field et al. Self-management education and regular practitioner review for community interest company. As such, primary care of self management of chronic adults with asthma. Cochrane Database Syst Rev 2002(3):CD001117. trusts or general practice commissioning groups will disease and as such might benefit 26 Griffiths C, Taylor S, Feder G, Candy B, Ramsay J, Eldridge S, et al. from expansion of research Self management education by lay leaders for people with chronic need to pay for courses; they will need to consider funding in this area. conditions. (Protocol.) Cochrane Database Syst Rev 2005(1): carefully the opportunity costs of investing in this CD005108. Provenance and peer review: 27 Bethell HJN, Evans JA, Turner SC, Lewin RJP. The rise and fall of cardiac compared with other rehabilitation programmes for Non-commissioned; externally rehabilitation in the United Kingdom since 1998. J Public Health chronic disease.27 peer reviewed. 2007;29:57-61.

1256 BMJ | 16 JUNE 2007 | Volume 334 RESEARCH

Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: systematic review

Ros Collins, research fellow,1 Jane Burch, research fellow,1 Gillian Cranny, research fellow,1 Raquel Aguiar-Iba´n˜ez, research fellow in health economics,1 Dawn Craig, research fellow in health economics,1 Kath Wright, information officer,1 Elizabeth Berry, senior lecturer,2 Michael Gough, consultant vascular surgeon,3 Jos Kleijnen, director,4 Marie Westwood senior research fellow1

1Centre for Reviews and ABSTRACT angiography (with or without contrast) to contrast Dissemination, University of York, Objectives To determine the diagnostic accuracy of angiography, with half expressing no preference between York YO10 5DD duplex ultrasonography, magnetic resonance magnetic resonance angiography or duplex 2 Academic Unit of Medical angiography, and computed tomography angiography, ultrasonography (among patients with no Physics, University of Leeds, Leeds alone or in combination, for the assessment of lower limb contraindications for magnetic resonance angiography, 3Leeds Teaching Hospitals N peripheral arterial disease; to evaluate the impact of such as claustrophobia). Where data on adverse events HS Trust, Leeds these assessment methods on management of patients were available, magnetic resonance angiography was 4Kleijnen Systematic Reviews Ltd, and outcomes; and to evaluate the evidence regarding associated with the highest proportion of adverse events, York attitudes of patients to these technologies and but these were mild. The most severe adverse events, Correspondence to: Ros Collins summarise available data on adverse events. although rare, were mainly associated with contrast [email protected] Design Systematic review. angiography. doi: 10.1136/bmj.39217.473275.55 Methods Searches of 11 electronic databases (to April Conclusions Contrast enhanced magnetic resonance 2005), six journals, and reference lists of included papers angiography seems to be more specific than computed for relevant studies. Two reviewers independently tomography angiography (that is, better at ruling out selected studies, extracted data, and assessed quality. stenosis over 50%) and more sensitive than duplex Diagnostic accuracy studies were assessed for quality ultrasonography (that is, better at ruling in stenosis over with the QUADAS checklist. 50%) and was generally preferred by patients over Results 107 studies met the inclusion criteria; 58 studies contrast angiography. Computed tomography provided data on diagnostic accuracy, one on outcomes angiography was also preferred by patients over contrast in patients, four on attitudes of patients, and 44 on angiography; no data on patients’ preference between adverse events. Quality assessment highlighted duplex ultrasonography and contrast angiography were limitations in the methods and quality of reporting. Most available. Where available, contrast enhanced magnetic of the included studies reported results by arterial resonance angiography might be a viable alternative to segment, rather than by limb or by patient, which does not contrast angiography. account for the clustering of segments within patients, so specificities may be overstated. For the detection of INTRODUCTION stenosis of 50% or more in a lower limb vessel, contrast Lower limb peripheral arterial disease is the atheroma- enhanced magnetic resonance angiography had the tous narrowing or occlusion of an artery or arteries of the highest diagnostic accuracy with a median sensitivity of leg. If symptoms occur these may include intermittent 95% (range 92-99.5%) and median specificity of 97% claudication, ischaemic rest pain, ulceration, and (64-99%). The results were 91% (89-99%) and 91% (83- gangrene.1 Risk factors include advanced age, smoking, 97%) for computed tomography angiography and 88% hypertension, hyperlipidaemia, diabetes, obesity, and (80-98%) and 96% (89-99%) for duplex ultrasonography. family history.2 Management strategies differ for A controlled trial reported no significant differences in patients with intermittent claudication (often conserva- outcomes in patients after treatment plans based on tive management, with radiological or surgical inter- duplex ultrasonography alone or conventional contrast vention reserved for patients with reduced quality of angiography alone, though in 22% of patients life) and patients with limb threatening ischaemia, in supplementary contrast angiography was needed to form whom angioplasty, surgical revascularisation, or ampu- a treatment plan. The limited evidence available tation are usually required.3 The choice of intervention is suggested that patients preferred magnetic resonance governed by the severity of the disease and may involve

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contrast angiography to try to identify a technique Titles and abstracts identified and screened (n=8590) that is safer and more acceptable to patients but as

Not relevant (n=7940) effective as contrast angiography for the assessment of symptomatic peripheral arterial disease. Here we Potentially relevant papers ordered (n=650) present the systematic review of the evidence on effectiveness. The full report with economic evaluation is Could not be obtained (n=3) available elsewhere.4 Full copies retrieved and screened for inclusion (n=647) METHODS Excluded (n=540) We searched 11 databases (Medline, Embase, BIOS IS Previews, Science Citation Index, NTIS Database, Total number of included studies (n=107): Diagnostic accuracy (n=58) LILACS, SIGLE (system for information on grey lit- Management of patients (n=1) erature in Europe), Dissertation Abstracts Online, Patients' attitudes (n=4) Adverse events only (n=44) Inside Conferences, Pascal from 1996 to April 2005, and the Cochrane Database of Systematic Reviews, Issue 3, 2005), six key journals on imaging and vascular disease, and reference lists of included studies for pub- Fig 1 | Flow chart of studies through review process lished and unpublished data. No language restrictions were applied. Electronic searches were not limited by combined treatments. Thus patients with limb threaten- study design. Two reviewers conducted each stage of ing ischaemia require a detailed assessment for a suitable the review process (except in the case of foreign lan- treatment plan to be developed. guage studies), with disagreements resolved by con- Intra-arterial contrast angiography is regarded as the sensus or referral to a third reviewer. Full details of reference standard. The drawbacks are those asso- the review methods, including the search strategies, ciated with arterial puncture, ionising radiation, and are described elsewhere.4 Table 1 presents the inclu- potential nephrotoxicity of iodinated contrast agents. sion criteria for each section of the review. Several alternative imaging techniques are available, We used the QUADAS checklist to assess the quality including magnetic resonance angiography, computed of diagnostic accuracy studies.5 The results of diagnos- tomography angiography and duplex ultrasonogra- tic accuracy studies were analysed according to the phy. These techniques are less invasive than contrast imaging tests assessed (magnetic resonance angiogra- angiography, although computed tomography angio- phy, computed tomography angiography, or duplex graphy carries risks relating to ionising radiation, and ultrasonography). Magnetic resonance angiography both contrast enhanced magnetic resonance angiogra- technologies were further grouped by specific techni- phy and computed tomography angiography carry que (2D phase contrast, 2D time of flight, or contrast risks associated with the use of contrast agents. enhanced). We derived the sensitivity and specificity We carried out a systematic review to examine the for the detection of stenosis in arterial segments from evidence regarding the performance of magnetic reso- the 2×2 tables reported in each study. To account for nance angiography, computed tomography angiogra- values of zero in the 2×2 tables, we added 0.5 to all phy, and duplex ultrasonography as alternatives to cells.6 Heterogeneity was assessed with the Q statistic

Table 1 | Inclusion criteria for each of four sections of review of duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for assessment of patients with lower limb peripheral arterial disease

Impact on patient Diagnostic accuracy management/outcome Acceptability for patients Adverse events Study design Diagnostic cohort or case- Randomised controlled trial/ Studies of any design, Studies of any design, control controlled clinical trial excluding case reports excluding case reports Population Studies in ≥20 adults (≥ Studies in ≥20 adults (≥ Studies in ≥20 adults (≥ Studies in adults with 18 years) with symptoms 18 years) with symptoms 18 years) with symptoms symptoms indicating lower indicating lower limb indicating lower limb indicating lower limb limb peripheral arterial disease peripheral arterial disease peripheral arterial disease peripheral arterial disease Index tests/ Duplex ultrasonography, Duplex ultrasonography, Duplex ultrasonography, Duplex ultrasonography, interventions magnetic resonance magnetic resonance magnetic resonance magnetic resonance angiography, or computed angiography, or computed angiography, or computed angiography, or computed tomography angiography, tomography angiography, tomography angiography, tomography angiography, alone or in combination alone or in combination alone or in combination alone or in combination Reference standard Intra-arterial contrast NA NA NA angiography or findings at surgery/follow-up Outcomemeasures Sufficient information to Any treatment decision or long Any reported criteria relating to Adverseevents relatingtoindex construct 2×2 tables of test term outcome measure (for acceptability for patients testortocurrentlyusedcontrast performance example, graft/vessel patency agents after intervention, morbidity) NA=not applicable.

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Table 2 | Diagnostic accuracy for detection of stenosis 50% or more or occlusion with different assessment methods

Positive Negative No of Fontaine stage No of result result Sensitivity (%) (95% Specificity (%) (95% Study patients II/III/IV* (%) segments True False False True CI) CI) Contrast enhanced magnetic resonance angiography Cronbergw13 35 9/3/89 418 227 62 20 109 91.9 (87.8 to 95.0) 63.7 (56.1 to 70.9) Laissyw16 20 100/0/0 520 104 14 9 393 92.0 (85.4 to 96.3) 96.6 (94.3 to 98.1) Lenhartw17 45 NR 220 79 8 4 129 95.2 (88.1 to 98.7) 94.2 (88.8 to 97.4) Schaferw19 30 NR 576 138 13 9 416 93.9 (88.7 to 97.2) 97.0 (94.9 to 98.4) Steffensw21 50 NR 900 185 8 1 706 99.5 (97.0 to 100) 98.9 (97.8 to 99.5) Sueyoshiw22 23 83/17/0 423 67 3 2 351 97.1 (89.9 to 99.6) 99.2 (97.5 to 99.8) Wintererw23 76 87/13/0 1780 362 43 14 1361 96.3 (93.8 to 97.9) 96.9 (95.9 to 97.8) 2D time of flight magnetic resonance angiography Baumw2 155 NR 1188 527 101 100 460 84.1 (80.9 to 86.8) 82.0 (78.6 to 85.1) Hochw6 20 NR 544 161 37 44 302 78.5 (72.3 to 84.0) 89.1 (85.3 to 92.2) Hochw7 45 18/20/62 352 172 13 12 155 93.5 (88.9 to 96.6) 92.3 (87.1 to 95.8) Snidoww10 42 NR 378 80 76 7 215 92.0 (84.1 to 96.7) 73.9 (68.4 to 78.8) Yucelw12 25 0/84/16 206 65 16 6 119 91.5 (82.5 to 96.8) 88.1 (81.5 to 93.1) 2D phase contrast magnetic resonance angiography Steffensw1 115 100/0/0 253 229 5 5 14 97.9 (95.1 to 99.3) 73.7 (48.8 to 90.9) Computed tomography angiography Heuschmidw27 23 78/13/9 568 133 40 16 379 89.3 (83.1 to 93.7) 90.5 (87.2 to 93.1) Martinw28 41 NR 1312 327 61 38 886 89.6 (86.0 to 92.5) 93.6 (91.8 to 95.0) Pulsw30 31 97/3/0 186 56 17 7 106 88.9 (78.4 to 95.4) 86.2 (78.8 to 91.7) Riekerw31 50 74/12/14 327 111 20 3 193 97.4 (92.5 to 99.5) 90.6 (85.9 to 94.2) Catalanow26 50 6/48/46 1137 251 23 3 860 98.8 (96.6 to 99.8) 97.4 (96.1 to 98.3) Portugallerw29 50 62/4/34 740 240 80 21 399 92.0 (88.0 to 95.0) 83.3 (79.7 to 86.5) Duplex ultrasonography Alyw33 90 90/9/1 3108 404 27 34 2643 92.2 (89.3 to 94.6) 99.0 (98.5 to 99.3) Bergaminiw35 44 NR 404 94 13 24 273 79.7 (71.3 to 86.5) 95.5 (92.4 to 97.6) Hatsukamiw40 29 NR 243 73 6 12 152 85.9 (76.6 to 92.5) 96.2 (91.9 to 98.6) Linkew48 25 100/0/0 134 41 4 2 87 95.3 (84.2 to 99.4) 95.6 (89.1 to 98.8) Sensierw50 76 88/0/12 469 214 26 28 201 88.4 (83.7 to 92.2) 88.5 (83.7 to 92.4) El-Kayaliw55 44 NR 357 123 15 3 216 97.6 (93.2 to 99.5) 93.5 (89.5 to 96.3) Legematew58 61 80/16/3 918 179 30 33 676 84.4 (78.8 to 89.0) 95.8 (94.0 to 97.1) NR=not reported. *Stage II=intermittent claudication; stage III=ischaemic rest pain; stage IV=tissue loss.

and graphically with forest plots. Most studies pro- were several potential sources of bias. Spectrum bias vided data for more than one anatomical area (above may have been present; over 70% of studies did not knee, below knee, foot) or more than one threshold of include an appropriate range of patients (defined as stenosis (50%, 70%, occlusion). The number of arterial unselected, prospective adult patients with symptoms segments assessed per patient and their anatomical dis- indicating lower limb peripheral arterial disease) or tribution varied and was sometimes incompletely failed to provide sufficient details of the population; reported. Analyses were conducted with Meta-DiSc.7 48% of magnetic resonance angiography studies, 29% We have presented a narrative synthesis for studies of computed tomography angiography studies, and evaluating the impact of the method of assessment on 57% of duplex ultrasonography studies did not provide management and outcome in patients, attitudes of adequate details of selection criteria. Spectrum bias patients, and studies of adverse events. may underestimate or overestimate the accuracy of a test by investigating a selected population with regard RESULTS to the severity of disease, demographics, or The search strategy generated 8590 references, of comorbidity.5 Bias may occur when the delay between which 650 were considered to be potentially relevant; the index test and reference standard are long enough ultimately 107 met the inclusion criteria. Figure 1 for the disease to have progressed naturally; 20% of shows the flow of studies through the selection process. magnetic resonance angiography studies, 29% of computed tomography angiography studies, and 36% of Quality of diagnostic accuracy studies duplex ultrasonography studies did not report having All included studies were diagnostic cohorts and were less than a one month interval between the index test conducted in secondary or tertiary care settings. There and reference standard. Bias may also occur when the

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results of the index test are interpreted by someone magnetic resonance angiography,w1 11 evaluated 2D with prior knowledge of the results of the reference time of flight magnetic resonance angiography,w2-w12 test and vice versa. The index test results were inter- 14 evaluated contrast enhanced magnetic resonance preted without knowledge of the reference test results angiography,w8 w13-w25 7 evaluated computed tomogra- in 84% of magnetic resonance angiography studies and phy angiography,w26-w32 and 28 evaluated duplex 71% of duplex ultrasonography and computed tomo- ultrasonography.w4 w8 w33-w58 No studies evaluated 3D graphy angiography studies. The reference test results time of flight magnetic resonance angiography. Con- were interpreted without knowledge of the index test trast angiography was the reference standard in all stu- results in 84% of magnetic resonance angiography studies. As there was significant heterogeneity between dies, 82% of duplex ultrasonography studies, and 71% individual studies we did not pool data and have pre- of computed tomography angiography studies. sented results as medians (range). There is evidence that the availability of appropriate Most of the included studies reported results by clinical data increases the accuracy of interpretation.8 arterial segment, rather than by limb or by patient, The availability of clinical data was poorly reported, which does not account for the clustering of segments with only one study that evaluated magnetic resonance within patients. Therefore, the increased number of angiography and duplex ultrasonography reporting segments assessed is likely to increase the number of that clinical data were available when the imaging true negative test results, and thus the specificities may results were interpreted. Full details of included studies be overstated. We report results only for studies where and quality assessment are on www.york.ac.uk/inst/ data were reported by arterial segment. Full diagnostic accuracy results are available elsewhere.4 crd/projects/peripheralarterialdisease.htm. Whole leg Assessment of stenosis/occlusion Table 2 shows data for detection of stenosis 50% or Fifty eight diagnostic accuracy studies met the inclu- more or occlusion. Figures 2 and 3 show sensitivity sion criteria. One evaluated 2D phase contrast and specificity data, respectively. Contrast enhanced magnetic resonance angiography had the highest diag- Contrast enhanced magnetic resonance imaging Sensitivity (95% CI) nostic accuracy (seven studiesw13 w16 w17 w19 w21-w23), with Cronberg 0.92 (0.88 to 0.95) median sensitivity 95% (range 92-99.5%) and median Laissy 0.92 (0.85 to 0.96) specificity 97% (64-99%). One study had a low specifi- Lenhart 0.95 (0.88 to 0.99) city (64%) compared with the others; this was the only Schafer 0.94 (0.89 to 0.97) study to include assessment of foot vessels in the Steffens 0.99 (0.97 to 1.00) scan.w13 2D time of flight magnetic resonance angiogra- Sueyoshi 0.97 (0.90 to 1.00) phy was less accurate (five studiesw2 w6 w7 w10 w12), with Winterer 0.96 (0.94 to 0.98) median sensitivity 92% (79-94%) and median specifi- 2D time of flight magnetic resonance imaging city 88% (74-92%). The use of time of flight magnetic Baum 0.84 (0.81 to 0.87) resonance angiography has largely been superseded Hoch 0.79 (0.72 to 0.84) by contrast enhanced magnetic resonance angiogra- Hoch 0.93 (0.89 to 0.97) phy. Only one studyw1 evaluated 2D phase contrast Snidow 0.92 (0.84 to 0.97) magnetic resonance angiography and this reported Yucel 0.92 (0.83 to 0.97) sensitivity and specificity of 98% and 74%, respec- 2D phase contrast magnetic resonance imaging tively. Steffens 0.98 (0.95 to 0.99) Computed tomography angiography (six Computed tomography angiography studies,w26-w31 five of which used multidetector row Heuschmid 0.89 (0.83 to 0.94) computed tomography angiography) had median sen- Martin 0.90 (0.86 to 0.93) sitivity 91% (89-99%) and median specificity 91% (83- Puls 0.89 (0.78 to 0.95) 97%). Duplex ultrasonography (seven Rieker 0.97 (0.93 to 0.99) studiesw33 w35 w40 w48 w50 w55 w58 Catalano 0.99 (0.97 to 1.00) ) had median sensitivity Portugaller 0.92 (0.88 to 0.95) 88% (80-98%) and median specificity 96% (89-99%). Duplex ultrasonography The study with the lowest sensitivity (80%) was the Aly 0.92 (0.89 to 0.95) only study in this group with an unacceptable delay Bergamini 0.80 (0.71 to 0.87) (that is, over one month) between the index test and w35 Hatsukami 0.86 (0.77 to 0.92) reference standard. Linke 0.95 (0.84 to 0.99) Table 3 shows data for detection of occlusion. Fig- Sensier 0.88 (0.84 to 0.92) ures 4 and 5 show sensitivity and specificity data, El-Kayali 0.98 (0.93 to 1.00) respectively. Contrast enhanced magnetic resonance w17-w19 w21-w23 Legemate 0.84 (0.79 to 0.89) angiography (six studies ) had median sensitivity 94% (85-100%) and median specificity 99.2% 0 0.2 0.4 0.6 0.8 1 (97-99.8%). 2D time of flight magnetic resonance Sensitivit y angiography (four studiesw2 w6 w7, w12) had lower sensitivity; median 86% (77-100%) and comparable specifi- Fig 2 | Sensitivities for the detection of stenosis ≥50% or occlusion city; median 97% (85-98%). Computed tomography

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angiography (five studies,w26-w28 w30 w31 four of which median sensitivity and specificity were 88% and 95% used multidetector row computed tomography angio- above the kneew8 w35 w39 w40 w47 w55 w56 and 84% and 93% graphy) had median sensitivity 97% (89-100%) and below the knee.w35 w40 w43 w55 median specificity 99.6% (99-100%). Two studies assessed accuracy for the detection of Duplex ultrasonography (seven occlusion in the foot: one evaluated 2D time of flight studiesw33 w35 w40 w48 w50 w55 w58) had median sensitivity magnetic resonance angiographyw5 and the other con- 90% (74-94%), and median specificity 99% (96- trast enhanced magnetic resonance angiography.w24 100%). One study reported a notably low sensitivity Sensitivities were 86% and 79%, respectively, and spe- (74%)w48; of the three studies that reported Fontaine cificities 27% and 86%, respectively. One study classification (a system used to describe the severity assessed the accuracy of duplex ultrasonography for of peripheral arterial disease), this was the only study detecting target vessels suitable for surgery in the restricted to people with Fontaine stage II (intermittent foot, with sensitivity and specificity of 64% and 80% w42 claudication). respectively. Although there was limited evidence, these data suggest that these techniques may be less Above and below the knee accurate in the foot. Some studies provided separate results on diagnostic Impact of method of assessment on management and accuracy for arterial segments above and below the outcome knee. The accuracy of the different techniques was Only one controlled trial, a prospective assessment of similar for the detection of stenosis of 50% or more duplex ultrasonography using a historical control above and below the knee: with contrast enhanced group, met the inclusion criteria for assessing the magnetic resonance angiography the median sensitiv- impact of the assessment method on patients’ manage- ity and specificity were 87% and 93%, respectively, ment and outcome.w59 The study included consecutive above the kneew8 w14 w17 w20 and 83% and 92% below the patients with lower leg ischaemia whose treatment kneew15 w17 w24; with duplex ultrasonography the plans were based on the results of either duplex ultrasonography with contrast angiography where indi- Contrast enhanced magnetic resonance imaging Specificity (95% CI) cated (114 patients) or contrast angiography (control Cronberg 0.64 (0.56 to 0.71) group 113 patients). Laissy 0.97 (0.94 to 0.98) In 78% of cases the management plan was based on Lenhart 0.94 (0.89 to 0.97) duplex ultrasonography without the need for contrast Schafer 0.97 (0.95 to 0.98) angiography. There were no significant differences Steffens 0.99 (0.98 to 1.00) between the groups in terms of immediate and inter- Sueyoshi 0.99 (0.98 to 1.00) mediate outcomes. This trial seems to have been well Winterer 0.97 (0.96 to 0.98) conducted and the results are likely to be reliable. As it 2D time of flight magnetic resonance imaging used a historical control group, however, other factors Baum 0.82 (0.79 to 0.85) occurring within the timeframe of the trial may have Hoch 0.89 (0.85 to 0.92) affected the results. Treatment and characteristics of Hoch 0.92 (0.87 to 0.96) patients were not significantly different between the Snidow 0.74 (0.68 to 0.79) two groups, although the authors did not comment Yucel 0.88 (0.81 to 0.93) on some factors that could have influenced outcomes, 2D phase contrast magnetic resonance imaging such as the graft material used, continuation of smok- Steffens 0.74 (0.49 to 0.91) ing, and the use of antiplatelet drugs. Computed tomography angiography Heuschmid 0.90 (0.87 to 0.93) Patients’ attitudes Martin 0.94 (0.92 to 0.95) Four studies reported results relating to patients’ atti- Puls 0.86 (0.79 to 0.92) Rieker 0.91 (0.86 to 0.94) tudes. Two evaluated magnetic resonance angiogra- w60 w61 Catalano 0.97 (0.96 to 0.98) phy and contrast angiography, one duplex Portugaller 0.83 (0.80 to 0.87) ultrasonography and magnetic resonance w62 Duplex ultrasonography angiography, and one computed tomography Aly 0.99 (0.99 to 0.99) angiography, magnetic resonance angiography, and w63 Bergamini 0.95 (0.92 to 0.98) contrast angiography. Significantly more patients Hatsukami 0.96 (0.92 to 0.99) (28/30 patients) stated that they would prefer contrast Linke 0.96 (0.89 to 0.99) enhanced magnetic resonance angiography over con- Sensier 0.89 (0.84 to 0.92) trast angiography if they had to undergo testing again w60 El-Kayali 0.94 (0.90 to 0.96) in the future, and contrast enhanced magnetic reso- Legemate 0.96 (0.94 to 0.97) nance angiography scored significantly better on a scale that rated patients’ experience of the test com- 0 0.2 0.4 0.6 0.8 1 pared with contrast angiography (P=0.0001 and P= S pecificity 0.0002).w60 w61 Contrast angiography was reported as the most Fig 3 | Specificities for the detection of stenosis ≥50% or occlusion uncomfortable, followed by contrast enhanced

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magnetic resonance angiography, with computed w64-w107 reported results relating to adverse events. tomography angiography being the least uncomforta- The lack of reporting of data on adverse events cannot ble (P=0.016).w63 Fifty per cent of patients (who were be interpreted as no adverse events having occurred. not claustrophobic and had no metallic implants) had The criteria used in monitoring and recording adverse no preference between time of flight magnetic reso- events varied and were not always reported. These nance angiography or duplex ultrasonography (49/ results should therefore be regarded only as a guide 98 patients). Of those who did express a preference, to the spectrum of adverse events reported and not as most preferred time of flight magnetic resonance an accurate assessment of their frequency. angiography (40/49 patients).w62 The most commonly reported adverse events were Within the same population there was no significant minor pain or discomfort during or immediately after difference between time of flight magnetic resonance the procedure (17% for 2D time of flight magnetic reso- angiography and duplex ultrasonography on a scale nance angiography (2/12 patients), 22% for duplex that rated how “bothersome” the tests were.w62 While ultrasonography (22/98 patients), and up to 10% for some of the surveys potentially suffered from recall or contrast enhanced magnetic resonance angiography sequential bias, they were generally well conducted (10/98 patients)), acute symptoms in the digestive sys- and the results are probably reliable. As the studies tem associated with contrast enhanced magnetic reso- included only patients who were suitable for magnetic nance angiography (up to 10% (2/20) patients), anxiety resonance angiography, the results cannot be general- associated with 2D time of flight magnetic resonance ised to patients who are not suitable for magnetic reso- angiography (10% (4/40) patients), and acute adverse nance angiography, such as those with claustrophobia events in the central and peripheral nervous system or metallic implants. associated with contrast enhanced magnetic resonance angiography (up to 10% (2/20) patients). Adverse events The highest proportion of adverse events was Nine of the diagnostic accuracy reported for magnetic resonance angiography. Major studies,w4-w7 w19 w28 w29 w32 w37 two studies reporting adverse events (death and severe vascular adverse patient attitudes,w60 w62 and 44 additional studies, events), however, were reported in a higher proportion

Table 3 | Diagnostic accuracy for detection of occlusion with different assessment methods

Positive Negative No of Fontaine stage No of result result Sensitivity (%) (95% Specificity (%) (95% Study patients II/III/IV* (%) segments True False False True CI) CI) Contrast enhanced magnetic resonance angiography Lenhartw17 45 NR 220 54 2 4 160 93.1 (83.3 to 98.1) 98.8 (95.6 to 99.9) Meaneyw18 20 100/0/0 630 83 16 15 516 84.7 (76.0 to 91.2) 97.0 (95.2 to 98.3) Schaferw19 30 NR 576 72 1 5 498 93.5 (85.5 to 97.9) 99.8 (98.9 to 100) Steffensw21 50 NR 900 85 7 4 804 95.5 (88.9 to 98.8) 99.1 (98.2 to 99.7) Sueyoshiw22 23 83/17/0 423 39 1 0 383 100 (91.0 to 100) 99.7 (98.6 to 100) Wintererw23 76 87/13/0 1780 255 11 13 1501 95.1 (91.8 to 97.4) 99.3 (98.7 to 99.6) 2D time of flight magnetic resonance angiography Baumw2 155 NR 1188 322 118 76 672 80.9 (76.7 to 84.6) 85.1 (82.4 to 87.5) Hochw6 20 NR 544 103 17 31 393 76.9 (68.8 to 83.7) 95.9 (93.4 to 97.6) Hochw7 45 18/20/62 352 101 4 11 236 90.2 (83.1 to 95.0) 98.3 (95.8 to 99.5) Yucelw12 25 0/84/16 206 40 4 0 162 100 (91.2 to 100) 97.6 (93.9 to 99.3) Computed tomography angiography Heuschmidw27 23 78/13/9 568 49 6 5 508 90.7 (79.7 to 96.9) 98.8 (97.5 to 99.6) Martinw28 41 NR 1312 202 2 26 1082 88.6 (83.7 to 92.4) 99.8 (99.3 to 100) Pulsw30 31 97/3/0 186 13 0 0 173 100 (75.3 to 100) 100 (97.9 to 100) Riekerw31 50 74/12/14 327 61 1 1 264 98.4 (91.3 to 100) 99.6 (97.9 to 100) Catalanow26 50 6/48/46 1137 170 5 5 957 97.1 (93.5 to 99.1) 99.5 (98.8 to 99.8) Duplex ultrasonography Alyw33 90 90/9/1 3108 272 18 25 2793 91.6 (87.8 to 94.5) 99.4 (99.0 to 99.6) Bergaminiw35 44 NR 404 76 10 13 305 85.4 (76.3 to 92.0) 96.8 (94.2 to 98.5) Hatsukamiw40 29 NR 233 51 3 6 173 89.5 (78.5 to 96.0) 98.3 (95.1 to 99.6) Linkew48 25 100/0/0 134 14 0 5 115 73.7 (48.8 to 90.9) 100 (96.8 to 100) Sensierw50 76 88/0/12 469 166 11 21 271 88.8 (83.3 to 92.9) 96.1 (93.1 to 98.0) Zeuchnerw53 54 NR 322 50 3 3 266 94.3 (84.3 to 98.8) 98.9 (96.8 to 99.8) Legematew58 61 80/16/3 918 103 6 9 800 92.0 (85.3 to 96.3) 99.3 (98.4 to 99.7) NR=not reported. *Stage II=intermittent claudication; stage III=ischaemic rest pain; stage IV=tissue loss.

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Contrast enhanced magnetic resonance imaging Sensitivity (95% CI) detection of (50% or more) stenosis or occlusion, with Lenhart 0.93 (0.83 to 0.98) most studies reporting sensitivities and specificities of Meaney 0.85 (0.76 to 0.91) over 90% (based on a “per segment” rather than “per Schafer 0.94 (0.85 to 0.98) patient” analysis). Magnetic resonance angiography Steffens 0.96 (0.89 to 0.99) was associated with the highest proportion of adverse Sueyoshi 1.00 (0.91 to 1.00) events, although these were generally mild, with the Winterer 0.95 (0.92 to 0.97) most severe events associated with contrast angiogra- 2D time of flight magnetic resonance imaging phy. The results of three surveys on patients’ attitudes Baum 0.81 (0.77 to 0.85) showed that patients who had no contraindications for Hoch 0.77 (0.69 to 0.84) magnetic resonance angiography preferred magnetic Hoch 0.90 (0.83 to 0.95) resonance angiography to contrast angiography. Yucel 1.00 (0.91 to 1.00) The use of computed tomography angiography for Computed tomography angiography the assessment of peripheral arterial disease is a rela- Heuschmid 0.91 (0.80 to 0.97) tively recent development, and its contribution to Martin 0.89 (0.84 to 0.92) effective surgical planning remains to be explored. Puls 1.00 (0.75 to 1.00) Patients found computed tomography angiography Rieker 0.98 (0.91 to 1.00) less uncomfortable than contrast angiography or mag- Catalano 0.97 (0.93 to 0.99) netic resonance angiography, and only a few mild Duplex ultrasonography adverse events were reported. Aly 0.92 (0.88 to 0.94) The only controlled trial of the effectiveness of ima- Bergamini 0.85 (0.76 to 0.92) ging procedures, in terms of surgical planning and out- Hatsukami 0.89 (0.78 to 0.96) come of patients, found that duplex ultrasonography Linke 0.74 (0.49 to 0.91) and contrast angiography were comparable, a result Sensier 0.89 (0.83 to 0.93) that is seemingly at odds with poor estimates of the Zeuchner 0.94 (0.84 to 0.99) diagnostic accuracy for duplex ultrasonography. The Legemate 0.92 (0.85 to 0.96) sensitivity of duplex ultrasonography seems to be 0 0.2 0.4 0.6 0.8 1 inferior to both contrast enhanced magnetic resonance Sensitivity angiography and computed tomography angiography, which means that duplex ultrasonography may miss Fig 4 | Sensitivities for the detection of occlusion some significant stenoses. This may be of particular concern if duplex ultrasonography were to be used to screen patients before surgical planning. Duplex ultra- of patients who underwent contrast angiography, sonography, however, is unlikely to misclassify a although the overall proportion who experienced whole limb as “normal” and thus inappropriately major adverse events was low (severe vascular adverse screen out a patient from further investigation. Fifty events: contrast angiography 5% (1/19 patients); con- per cent of patients expressed no preference between trast enhanced magnetic resonance angiography 0.5% time of flight magnetic resonance angiography or (2/435 patients)). There were two deaths: one with con- duplex ultrasonography, and those who did generally trast angiography and one with contrast enhanced preferred time of flight magnetic resonance angiogra- magnetic resonance angiography. phy. We had no data on patients’ preferences between Studies reported adverse events related to the con- contrast enhanced magnetic resonance angiography trast agent for a small proportion of patients in relation and duplex ultrasonography. Some studies reported to contrast angiography (acute renal failure in 10% (4/ minor adverse events associated with duplex ultraso- 42) of patients with baseline chronic renal insuffi- nography—namely, anxiety or minor pain or discom- ciency) and contrast enhanced magnetic resonance fort during or immediately after the procedure. angiography (acute renal failure: 1% (3/218) of patients The area of leg assessed probably affects diagnostic with baseline chronic renal insufficiency; acute change performance. Contrast enhanced magnetic resonance in renal function: 1% (2/136 patients); severe unspeci- angiography and duplex ultrasonography were less fied adverse events related to contrast agent: up to 1% accurate for detecting stenoses in the foot. There was (5/641 patients)). In one study, which was specifically insufficient evidence to judge computed tomography designed to evaluate the dose response and safety of angiography. The assessment of potential outflow ves- one contrast agent (gadofosveset trisodium),w83 a high sels in the foot is known to be problematic9 and war- proportion of patients (25%; 59/238) experienced rants further research, particularly with respect to unspecified adverse events related to the contrast newer technologies such as computed tomography agent after contrast enhanced magnetic resonance angiography. Separate data on calf vessels and foot ves- angiography. sels are required as the inclusion of foot vessels in below knee imaging may lower the accuracy of results. DISCUSSION Key findings Strengths and weaknesses of the review Contrast enhanced magnetic resonance angiography is We conducted extensive literature searches to locate the most accurate diagnostic technique for the all relevant studies. The possibility of publication bias

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remains a potential problem for all systematic reviews. any conclusions are not likely to be affected. The esti- The extent to which publication bias is an issue for mates of specificity derived from this type of study may diagnostic studies remains unclear as such studies mea- be raised as increasing the number of segments sure the agreement between the results of the index test assessed is likely to increase the number of true nega- and the reference standard, rather than assessing tives. whether there is a significant difference in outcome We did not collect data on variability between obser- between an intervention and control group. Studies vers, although we note that the methods used to ascer- reporting higher estimates of test performance are tain degree of stenosis were not generally well reported more likely to be published, but the extent to which and few studies directly measured such variability. this occurs is unclear. Similarly, tests might not per- This is an important issue in the evaluation of tests form as well in the clinical setting as indicated by that require subjective interpretation,10 and further reports from research studies. investigation of its effects on estimates of the accuracy Our review was limited by the lack of high quality, of vascular imaging techniques is needed. well reported studies. We found only one controlled The field of vascular imaging research is evolving trial, which used a historical control group that could rapidly, particularly in relation to the use of computed be subject to bias. Most studies that provided data on tomography angiography, which is a relatively recent diagnostic accuracy had small sample sizes (median development in the assessment of peripheral arterial 41.5, range 20-183) and reported results on a per seg- disease. We did not find any study investigating the ment rather than per patient basis. Our review there- diagnostic accuracy of the new 64 slice computed fore provides information on the ability of these tomography angiography as this is a very new devel- techniques to detect stenosis within particular arterial opment. Our results represent the imaging techniques segments but not for determining the presence or available at the time the primary studies were under- absence of disease on a per patient or per limb basis. taken and will become out of date as new techniques Few included studies reported these data. Analysis by emerge. segment also means that the estimates of the 95% con- Implications for clinical practice fidence intervals for sensitivity and specificity do not account for the clustering of segments within patients. From data that reported the accuracy of the imaging tests at assessing arterial segments, rather than the This would also affect statistical testing of heterogene- whole limb or areas of the limb, contrast enhanced ity, but given the considerable heterogeneity observed, magnetic resonance angiography seemed to have better overall diagnostic accuracy than computed tomo- Contrast enhanced magnetic resonance imaging Specificity (95% CI) graphy angiography and duplex ultrasonography, and Lenhart 0.99 (0.96 to 1.00) was preferred by patients over conventional angiogra- Meaney 0.97 (0.95 to 0.98) phy. It might therefore be a viable alternative to con- Schafer 1.00 (0.99 to 1.00) ventional contrast angiography for assessing patients Steffens 0.99 (0.98 to 1.00) with peripheral arterial disease before treatment. We Sueyoshi 1.00 (0.99 to 1.00) could not identify enough data to assess the effective- Winterer 0.99 (0.99 to 1.00) ness of the imaging tests in terms of surgical planning 2D time of flight magnetic resonance imaging and postoperative outcomes. In addition, the lack of Baum 0.85 (0.82 to 0.87) data on severity of disease and comorbidities reported Hoch 0.96 (0.93 to 0.98) by the included studies reduces the generalisability of Hoch 0.98 (0.96 to 1.00) these findings. Yucel 0.98 (0.94 to 0.99) Computed tomography angiography Implications for further research Heuschmid 0.99 (0.97 to 1.00) Quality assessment highlighted limitations in the qual- Martin 1.00 (0.99 to 1.00) ity of methods and reporting of many included studies. Puls 1.00 (0.98 to 1.00) Rieker 1.00 (0.98 to 1.00) Future evaluations of diagnostic tests should follow the Catalano 0.99 (0.99 to 1.00) STARD guidelines for reporting of diagnostic accu- 11 12 Duplex ultrasonography racy studies. They should also consider reporting Aly 0.99 (0.99 to 1.00) results by patient or by limb, as well as by segment, if Bergamini 0.97 (0.94 to 0.98) they would be relevant to clinical practice. Hatsukami 0.98 (0.95 to 1.00) Further research should assess the performance and Linke 1.00 (0.97 to 1.00) adverse effects of the imaging tests on different sub- Sensier 0.96 (0.93 to 0.98) groups of patients, particularly those who may be at Zeuchner 0.99 (0.97 to 1.00) higher risk of certain adverse events, such as those Legemate 0.99 (0.98 to 1.00) with diabetes and renal insufficiency. Additional separate data are required regarding the performance of the 0 0.2 0.4 0.6 0.8 1 different imaging tests for assessing calf and foot ves- Specificity sels. The use of newer technologies, such as computed tomography angiography, for the assessment of per- Fig 5 | Specificities for the detection of occlusion ipheral arterial disease should be assessed.

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Contributors: RC (guarantor) was responsible for study selection, data WHAT IS ALREADY KNOWN ON THIS TOPIC extraction, validity assessment, data analysis, and writing the paper. JB was Severity of disease determines the management strategy for involved in study selection, data extraction, validity assessment, data analysis, and writing the paper. GC, RA-I, and DC were involved in data extraction, validity symptomatic lower limb peripheral arterial disease, so assessment, data analysis, and writing the paper. KW devised the search detailed assessment of patients is needed before a suitable strategy, carried out the literature searches, and wrote the search methods treatment plan can be developed sections of the paper. EB provided advice on technical issues and commented Intra-arterial contrast angiography is regarded as the on drafts of the paper. MG provided clinical advice and commented on drafts of reference standard investigation for the assessment of the paper. JK provided advice and commented on drafts of the paper. MW peripheral arterial disease provided input at all stages, commented on drafts of the paper, and took overall responsibility for the review. WHAT THIS STUDY ADDS Funding: Health Technology Assessment Programme (project No 03/07/04). The views and opinions expressed herein are those of the authors and do not Contrast enhanced magnetic resonance angiography has necessarily reflect those of the Department of Health. better overall diagnostic accuracy than computed Competing interests: EB is now director of a company that undertakes tomography angiography or duplex ultrasonography and is consulting associated with medical imaging research. Neither she nor JK generally preferred by patients over conventional contrast received payment for their contributions to this review. angiography Ethical approval: Not required.

1 Beard J. Chronic lower limb ischaemia. BMJ 2000;320:854-7. 2 Drug treatment of peripheral arterial disease. Bandolier 1996:29-34. Data on the influence of imaging technologies on the www.jr2.ox.ac.uk/bandolier/band29/b29-4.html. surgical planning and postoperative outcome for 3 Management of peripheral arterial disease (PAD). TransAtlantic Inter- patients with peripheral arterial disease are urgently Society Consensus (TASC). 2005. www.tasc-pad.org/html/ homepage.htm. needed. A simple comparison of the accuracy of a tech- 4 Collins R, Cranny G, Burch J, Aguiar-IbáñezR,CraigD,WrightK,etal.A nique for defining the degree of stenosis cannot fully systematic review of duplex ultrasound, magnetic resonance assess the ability of a procedure to produce the “vascu- angiography and computed tomography angiography for the ” diagnosis and assessment of symptomatic, lower limb peripheral lar road map as factors such as length and grouping of arterial disease. Health Technol Assess 2007;11:1-202. stenoses are not considered. In addition a comparative 5 Whiting P, Rutjes A, Reitsma J, Bossuyt P, Kleijnen J. The development diagnostic accuracy study assumes that the result of the of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol reference standard investigation (in this case contrast 2003;3. www.biomedcentral.com/1471-2288/3/25. angiography) is always correct. Therefore, an evalua- 6 Moses L, Shapiro D, Littenberg B. Combining independent studies of tion with this method can never find that the new tech- a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med nology (index test) gives superior information to that 1993;12:1293-316. provided by current practice (reference standard). 7 ZamoraJ,MurielA,AbrairaV.Meta-DiSc for Windows: a software The most reliable and appropriate method for package for the meta-analysis of diagnostic tests [computer programme]. In: XI Cochrane Colloquium. Barcelona; 2003. www. obtaining comparative data on different testing options hrc.es/investigacion/metadisc.html. would be a randomised controlled trial designed to 8 Loy CT, Irwig L. Accuracy of diagnostic tests read with and without provide information on the influence of tests on deci- clinical information: a systematic review. JAMA 2004;292:1602-9. 9 UngerEC,SchillingJD,AwadAN,McIntyreKE,YoshinoMT,PondGD, sions about treatment and outcomes in patients with et al. MR angiography of the foot and ankle. J Magn Reson Imaging peripheral arterial disease. Data on health economics 1995;5:1-5. could be collected simultaneously. There may be ethi- 10 Brealey S, Westwood ME. Are you reading what we are reading? The effect of who interprets medical images on estimates of diagnostic cal objections to a randomised controlled trial, such as test accuracy in systematic reviews. Br J Radiol 2007 (in press). the withholding of an available test, particularly when 11 Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, it is a routine part of assessment of peripheral arterial Irwig LM, et al. Towards complete and accurate reporting of studies of disease in the institution involved in the study. Such a diagnostic accuracy: the STARD initiative. BMJ 2003;326:41-4. 12 Bossuyt PMM, Reitsma JB, Bruns D, Gatsonis C, Glasziou P, Irwig L, trial would be difficult because of the refinements in et al. The STARD statement for reporting studies of diagnostic technology over time, the availability of the technolo- accuracy: explanation and elaboration. AnnInternMed2003;138: w1-12. gies, and the potentially large sample size required. A large multicentre trial might be necessary. Accepted: 10 April 2007

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Diagnostic scopeof and exposure toprimarycarephysicians in Australia, New Zealand, and the United States: cross sectional analysis of results from three national surveys

Andrew B Bindman, professor,1 Christopher B Forrest, professor,2 Helena Britt, associate professor and director,3 Peter Crampton, professor,4 Azeem Majeed professor5

1Division of General Internal ABSTRACT organisational characteristics of healthcare systems Medicine, University of California Objectives To compare mix of patients, scope of practice, support primary care practice, defined as accessibility, San Francisco, San Francisco and duration of visit in primary care physicians in General Hospital, 1001 Potrero longitudinality, comprehensiveness, coordination, 2 Avenue, San Francisco, Australia, New Zealand, and the United States. family centredness, and community orientation. Lim- CA 94110, USA Design Comparison of three comparable cross sectional ited research has been done on the clinical content and 2Department of Pediatrics, surveys performed in 2001-2. Physicians completed a duration of visits in primary care across countries.34 ’ Children sHospitalof questionnaire on patients’ demographics, diagnoses, and Philadelphia, 3400 Civic Center We sought to characterise the diagnostic scope of and Boulevard, Abramson 1335, duration of visit. exposure to primary care in three countries—Austra- Philadelphia, PA 19104, USA Setting Primary care practice. lia, New Zealand, and the United States—that vary in 3Australian GP Statistics and Participants 79 790 office visits in Australia, 10 064 in the supply of primary care physicians, the accessibility Classification Centre, University of Sydney, Westmead Hospital, 2145 New Zealand, and 25 838 in the US. to primary care through health insurance, and the role NSW, Australia Main outcome measures Diagnostic codes were mapped of primary care physicians as gatekeepers to specialty 4University of Otago, Department to the Johns Hopkins expanded diagnostic clusters. care. of Public Health, Wellington Scope of practice was defined as the number of expanded Of the three countries studied, Australia has the School of Medicine and Health Sciences, PO Box 7343, diagnostic clusters accounting for 75% of all managed greatest number of primary care physicians per Wellington, New Zealand problems related to morbidity. Exposure to primary care 100 000 population (112) and the largest proportion 5Department of Primary Care and was calculated from duration of visits recorded by the (56%) of physicians trained in primary care specialties Social Medicine, Imperial College physician, and reports on rates of visits to primary care for (table 1). In Australia and New Zealand, primary care London, London each country. physicians are trained as general practitioners. In the Correspondence to: A B Bindman [email protected] Results In each country, primary care physicians US, general internists, general paediatricians, and managed an average of 1.4 morbidity related problems family practitioners all contribute to the pool of pri- doi: 10.1136/bmj.39203.658970.55 per visit. In the US, 46 expanded diagnostic clusters mary care physicians. accounted for 75% of problems managed compared with In the US universal health insurance that covers 52 in Australia, and 57 in New Zealand. Correlations in the access to primary care is not available for people under frequencies of managed health problems between 65 years, as it is in New Zealand and Australia. During countries were high (0.87-0.97 for pairwise the study period about 41 million Americans14 (15% of comparisons). Though primary care visits were longer in the total population) were uninsured and another 16 the US than in New Zealand and Australia, the per capita million adults aged 19-64 were underinsured.15 These annual exposure to primary care physicians in the US (29. individuals use primary medical care services, but at a 7 minutes) was about half of that in New Zealand (55. lower rate than they would if they had insurance.16 The 5 minutes) and about a third of that in Australia (83. national insurance benefits in New Zealand and Aus- 4 minutes) because of higher rates of visits to primary care tralia include cost sharing except for some low income in these countries. patients. A portion of the population has private insur- Conclusions Despite differences in the supply and ance to supplement public coverage, but private insur- financing of primary care across countries, many aspects ance does not typically cover primary care services. of the clinical practice of primary care physicians are In Australia and New Zealand, primary care physi- remarkably similar in Australia, New Zealand, and the US. cians serve as gatekeepers who coordinate and manage access to specialists through their referrals. Some INTRODUCTION health plans in the US require patients to use primary Previous studies show that the strength of a country’s care physicians to access specialty care, but this prac- primary care infrastructure is positively associated tice has been decreasing in recent years, and many with health outcomes and negatively associated with patients access specialty care services directly.17 healthcare costs.1 In general, these studies have relied We hypothesised that there would be substantial on experts to rate the degree to which policies and overlap in the practice of primary care across the

three countries, but key differences in the US health- We calculated national estimates using weights that care system would contribute to some observed differ- accounted for the complex survey design. ences. For example, we expected that the range of The NatMedCa survey was performed in New Zeal- problems managed in primary care would be narrower and in 2001-2 among a nationally representative prob- in the US because of the greater proportion of specialist ability sample of general practitioners and patients’ physicians in their healthcare system and more direct visits.20 For two periods of one week, each selected gen- access to specialty care for patients. We also expected eral practitioner completed a questionnaire for a 25% that differences in the US physician workforce, in com- systematic sample of patients’ visits. The questionnaire bination with a higher proportion of uninsured people, was adapted from the NAMCS administered in the US. would contribute to a lower per capita exposure time to To obtain a nationally representative sample, the sur- primary care physicians in the US than in Australia and vey sampled geographic locations and sampled gen- New Zealand. eral practitioners from locations stratified by type of organisation and by whether the practice was in a METHODS rural or urban setting. General practitioners and visits We used three independent nationally representative were weighted take account of different sampling prob- cross sectional surveys to compare mix of patients, abilities. scope of practice, and duration of visit among primary Analysis was limited to office based face to face care physicians in Australia, New Zealand, and the US. encounters in which the physician recorded one or We used the bettering the evaluation and care of health more diagnosis codes for morbidities treated during (BEACH) survey in Australia; the national primary the visit. We excluded visits in which physicians medical care survey (NatMedCa) in New Zealand; recorded only administrative, process, or preventive and the national ambulatory medical care survey care codes. Administrative codes are used in the US (NAMCS) in the US. The questionnaires include to indicate a personal or family history of a disease or items on whether the encounter is for a new or fol- an abnormal laboratory or other test result. Process low-up patient, patients’ demographics and diagnoses, codes are used in Australia and New Zealand to record and duration of visit. The reporting periods are spread diagnostic and treatment actions such cardiography or evenly throughout the year to reflect seasonal differ- immunisation. We intended to describe preventive care practices for activities such as immunisations, rou- ences. tine health supervision, and cancer screening; however BEACH is a continuous national survey in which a preventive care is not well described by diagnostic random sample of about 1000 of Australia’s 17 500 18 codes and differences in how preventive care is general practitioners participate each year. Partici- recorded in the classification systems used across coun- pating general practitioners complete (on paper tries made this problematic. Physicians recorded diag- encounter forms) information regarding 100 consecu- noses in free text and trained coders converted these tive encounters with patients. Each general practi- into the classification system used in that country. In ’ tioner s encounters are weighted according to their Australia up to four free text diagnoses were classified clinical activity as measured through submitted claims according to the International classification of primary for the previous three month period. For this study, we care, version 2 (ICPC-2).21 In New Zealand up to four used data from the 12 month period 2001-2. diagnoses were classified into Read codes.22 In the US, The NAMCS is a national annual survey of office up to three diagnoses were coded in ICD-9-CM (inter- based practice in the US.19 Physicians are sampled national classification of disease, 9th revision, clinical with a multistage probability design that involves pri- modification).23 To create a common taxonomy for mary sampling units, practices within those units, and this study, we re-assigned all diagnostic codes to an patients’ visits within practices. Depending on the size expanded diagnostic cluster. These clusters are clini- of their practice, participating physicians contribute cally homogeneous groups of diagnostic codes that anywhere from 20% to 100% of their encounters dur- were developed by Johns Hopkins University.24 The ing the one week study period. For this study, we used original grouping algorithm was developed from the 2001 and 2002 samples and included physicians ICD-9-CM For this project, three of the authors, who whose specialties were general internal medicine, gen- are practising primary care physicians, and a separate eral paediatrics, family practice, or general practice. primary care physician in Australia, assisted in creating

Table 1 | Characteristics of primary care by country, 2001-2

Australia New Zealand United States Primary care physicians/100 000 population 1125 787 879 Percentage of primary care physicians 565 427 369 Percentage of population uninsured for primary care 0 0 1510 Percentage with primary care gatekeeping for specialty care 100 100 3811 Mean No of primary care visits/person/year 5.26 3.78 1.812* *Using methods described by Forrest and Whelan.13 page 2 of 6 BMJ | ONLINE FIRST | bmj.com RESEARCH

250 primary care for each country by multiplying the aver- Australia age duration times of primary care visits by the average 200 number of primary care visits per person for the same New Zealand time period derived from separate sources. 150 Visits per 1000 We age standardised results for the US and New United States 100 Zealand to the Australian population using age cate- gories of 0-4, 5-14, 15-25, 25-34, 35-44, 45-54, 55-64, 50 65-74, and ≥75. Because our parameter of the number of problems managed that comprise 75% of problems 0 seen in primary care was a quartile (75th centile of the Eye Skin distribution of diagnosis), we used a bootstrap method Renal 25 Infections Respiratory to estimate the confidence interval. Neurological Psychosocial Malignancies Genitourinary Endocrinology Reconstructive General surgery Cardiovascular HaematologicalRheumatological Ear/nose/throatMusculoskeletal Allergy-immunologyFemale reproductive RESULTS Gastrointestinal/hepatic The surveys included 79 790 office based visits to pri- General signs and symptoms mary care in Australia, 10 064 in New Zealand, and 25 838 in the US. The excluded visits, in which only Fig 1 | Age standardised frequency of health problems managed in primary care in Australia, an administrative or preventive care code was New Zealand, and the US: 2001-2 recorded, ranged from 7% in New Zealand to 21% in the US (table 2). The remaining visits involved the a linkage to the expanded diagnostic cluster taxonomy management of at least one medical problem. Patients for Read codes used in New Zealand and ICPC-2 used aged 65 years or older accounted for similar propor- in Australia. Match rates between diagnostic codes and tions of total visits in each country, but a greater pro- expanded diagnostic clusters were 100% for the Aus- portion of visits in the US involved children (30%) than tralia and US datasets and 96% for the New Zealand in Australia (17%) or New Zealand (27%). Females dataset. accounted for more than half of the visits to primary care, and new patients comprised less than 10% of the We defined a problem managed as a unique visits in each country. expanded diagnostic cluster within a visit. To charac- In each country primary care physicians dealt with terise the scope of primary care practice in each coun- an average of 1.4 problems per visit. Those in the US, try, we calculated the minimum number of expanded however, managed a narrower range of problems than diagnostic clusters that accounted for 75% of the pro- their counterparts in New Zealand and Australia. In blems managed in primary care. This provided us with the US, 46 (95% confidence interval 45 to 47) condi- a means to summarise the comprehensiveness of pri- tions accounted for 75% of problems managed in primary care practice in each country without the compli- mary care compared with 52 (52 to 53) in Australia and cating noise introduced by low frequency problems 57 (56 to 59) in New Zealand. that skewed the distribution of problems managed in The relative frequency of health problems managed each country. We interpreted the analysis of the 75% of in primary care was similar across the study countries problems managed according to the principle that the (fig 1). Correlations in the frequencies of managed higher the number of problems the greater the compre- health problems between countries were 0.87 for the hensiveness of practice. pairwise comparison between US and New Zealand, We recorded duration of visit in minutes of face to 0.90 between Australia and the US, and 0.97 between face time between a patient and physician. We US and Australia. One of the most striking differences excluded time spent waiting to see the physician, time was the higher rates of visits for endocrine and cardio- receiving care from someone other than the physician, vascular problems in the US compared with Australia and time in documenting care in the medical record. and New Zealand. Nearly 18 per 1000 visits in the US We calculated the annual per person exposure to were for obesity; almost twice the rate for this

Table 2 | Demographics of patients as weighted* percentage of primary care visits by country, 2001-2

Australia (n=114 402) New Zealand (n=15 523) United States (n=42 144) Excluded† 13 7 21 Visits by patients who are: 0-17 years 17 27 30 18-64 years 60 52 47 ≥65 years 23 22 23 Female 57 57 56 New patients 9 8 7 *Sampling weights that were specific to each country were applied to account for the complex survey designs to obtain national probability estimates of visits to primary care in each country. †Visits for administrative, process, or preventive care services only.

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160 refer for specialty services results in some patients see- Australia ing only specialists for ambulatory care services.26 Our New Zealand Minutes 120 results extend these findings to suggest that the avail- United States ability of specialist physicians might also contribute to defining the range of problems managed in primary 80 care. For example, compared with Australia and New Zealand, the US has lower rates of visits in primary care 40 for the management of reproductive problems in women. The US is also the only country of the three 0 Total Male Female 0-17 18-64 >64 that provides most women with direct access to gynae- cologists. The presence of general internists and gen- Age (years) eral paediatricians among US primary care physicians may contribute to a narrower diagnostic scope of prac- Fig 2 | Mean per capita annual exposure to primary care tice in the US. Differences in rates of visits for specific physicians by country and demographic subgroups: 2001-2 problems, such as cardiovascular disease in the US, might also reflect national differences in the prevalence condition in Australia (11.3) and New Zealand (9.1). of conditions or health seeking behaviour. Unfortu- This is also reflected in substantially greater rates of nately, our data do not allow us to determine this. visits per 1000 in the US for diabetes (64.0) and hyperlipidaemia (59.2) than in Australia (31.0 and 32.2, Exposure to primary care respectively) and New Zealand (25.9 and 11.7, respec- The biggest difference in practice across the three tively). study countries is the substantially shorter time per The average duration of a visit was about 10% longer capita in the US. Annually, the average American in the US than in Australia and New Zealand. They receives a little more than half the exposure to primary were 16.5 minutes (16.4 to 16.6) in the US compared care physicians than people in New Zealand and just with 15.0 minutes (14.3 to 15.6) in New Zealand and over a third of that in Australia. This difference may 14.9 minutes (14.6 to 15.2) in Australia. Visit lengths have real consequences in terms of preventive care were longer in the US for all age and sex groups. and management of chronic conditions. The provision Because the average number of primary care visits of prevention services recommended by the US Pre- per capita was greater in New Zealand and Australia, vention Services Task Force requires an estimated however, the per capita annual exposure to primary average of 37 minutes a year for children and care physicians was substantially lower in the US. 40 minutes for adults.27 Not only does the time demand The mean time spent per year in primary care was 29. for such services exceed the annual time available to 7 minutes (29.5 to 29.9) in the US, 55.5 minutes (52.8 to the average American in primary care, it does not con- 57.8) in New Zealand, and 83.4 minutes (81.9 to 84.8) sider the average additional need of 20-40 minutes a in Australia (fig 2). year for each chronic condition a person may have.28 More than half of US primary care physicians’ time is DISCUSSION spent on the management of acute conditions, and this Despite differences in the supply and financing across role further limits their capacity to meet the prevention countries, many aspects of the clinical practice of pri- and chronic care needs of their patients.29 mary care physicians are remarkably similar in Austra- Of the three countries we studied, only Australia lia, New Zealand, and the US. There is a high level of approaches a per capita exposure to primary care that agreement in primary care across countries in the num- could reasonably be expected to meet patients’ ber of problems that are managed per visit, the types of demands for preventive and acute and chronic care problems that are managed, and the duration of visits. needs. The severe shortfall of available time in primary care for prevention and chronic care management in Diagnostic scope of practice the US could partially explain why the US does not The similarity in the types of problems managed have health outcomes that correspond to its overall within primary care across countries implies that pri- investment in health care.30 mary care practice is a definable area of clinical work and not merely the activities that are not performed by Limitations specialists. The finding that the range is narrower in the Exclusion of visits in which only administrative, pro- US than in Australia and New Zealand, however, also cess, or preventive care codes were recorded limits our suggests that the comprehensiveness of primary care is ability to count the amount of preventive care that is influenced at the margin by the amount of specialisa- actually occurring in primary care. Even with this tion in the healthcare system. The use of specialists is exclusion, however, we have an accurate estimate of greater in the US than in either Australia or New Zeal- the exposure to primary care by country. This estimate and. includes all visits, even those in which only preventive, The high proportion of specialist physicians in the administrative, or process codes would have been US in combination with the ability of patients to self recorded. page 4 of 6 BMJ | ONLINE FIRST | bmj.com RESEARCH

Funding: Commonwealth Fund. BEACH 2001-2 was funded by the Australian WHAT IS ALREADY KNOWN ON THIS TOPIC Government Department of Health and Ageing, AstraZeneca (Australia), The strength of a country’s primary care infrastructure is positively associated with health Aventis Pharma, Roche Products, Janssen-Cilag, and Merck Sharp and Dohme outcomes and negatively associated with healthcare costs (Australia). The NatMedCa survey was funded by the Health Research Council of New Zealand. The National Ambulatory Medical Care Survey is administered WHAT THIS STUDY ADDS and maintained by the National Center for Health Statistics of the US Department of Health and Human Services. The number and type of problems managed per primary care visit in Australia, New Zealand, Competing interests: None declared. and the United States are similar Ethical approval: Not required. Primary care is less comprehensive in the US than in Australia or New Zealand and the average American receives about half the exposure to primary care physicians compared with 1 Starfield B, Shi L. Policy relevant determinants of health: an people in New Zealand and about a third of that of people in Australia international perspective. Health Policy 2002;60:201-18. 2 Starfield B, Shi L, Macinko J. Contribution of primary care to health systems and health. Milbank Q 2005;83:457-502. 3 Okkes IM, Polderman GO, Fryer GE, Yamada T, Bujak M, Oskam SK, et al. The role of family practice in different health care systems. JFam As with any comparison between countries, our Pract 2002;51:72-3. results should be interpreted with caution. Firstly, we 4 Deveugele M, Derese A, van den Brin-Muinen A, Bensing J, De looked at only three countries and this limits its generali- Maeseneer J. Consultation length in general practice: cross sectional study in six European countries. BMJ 2002;325:472-7. sability. Secondly, although the data were derived from 5 Australian Institute of Health and Welfare. Australia’s health 2004: similar surveys with large samples, there were differ- the ninth biennial health report of the Australian Institute of Health and Welfare. Canberra: Australian Institute of Health and Welfare, ences in how some questions were asked and coded. 2004. (AUS 44.) We were careful to consider differences in the surveys 6 Medicine Australia. Medicare benefits schedule group statistics and to create common methods of analysis that would reports. Australia: Medicare Australia, 2001-2. www. medicareaustralia.gov.au/statistics/dyn_mbs/forms/mbsgtab4. limit the introduction of bias, but our results may still shtml. include measurement artefact. For example, the US 7 Medical Council of New Zealand. New Zealand medical workforce in 2002. Wellington: Medical Council of New Zealand, 2004. had the highest percentage of visits excluded from ana- 8SuttonF.Population-based funding for primary health care: methods lysis because they were coded only with administrative, and results. Wellington: Health Funding Authority, 2000. process, or preventive care codes. These visits may 9 United States General Accounting Office. Physician workforce: physician supply increased in metropolitan and nonmetropolitan reflect provision of primary medical care services that areas but geographic disparities persisted. 2003. http://frwebgate. had they been included would have widened our assess- access.gpo.gov/cgi-bin/useftp.cgi? IPaddress=162.140.64.21&filename=d04124.pdf&directory=/ ment of the scope of practice in the US relative to Aus- diskb/wais/data/gao. tralia and New Zealand. Thirdly, the available cross 10 Bhandari Shailesh. Health status, health insurance and health services utilization: 2001. Washington: US Census Bureau, 2006. sectional observational data limit our ability to draw cau- www.census.gov/prod/2006pubs/p70-106.pdf. sal inferences and lacked information that would allow 11 Forrest CB. Primary care gatekeeping and referrals: effective filter or us to determine how variation in practice is associated failed experiment? BMJ 2003;326:692-5. 12 National Center for Health Statistics. Ambulatory health care data. with differences in quality of care. None the less, our Atlanta, GA: Centers for Disease Control and Prevention, 2006. www. study is useful because most previous work has focused cdc.gov/nchs/about/major/ahcd/ahcd1.htm. 13 Forrest CB, Whelan EM. Primary care safety-net delivery sites in the on hospital based care and procedures. United States: a comparison of community health centers, hospital outpatient departments, and physicians’ offices. JAMA Summary 2000;284:2077-83. 14 Mills RJ. Health insurance coverage: 2001.Washington,DC:USDept Despite the markedly different approaches countries of Commerce, Economics, and Statistics Administration, US Census take towards funding and organising healthcare deliv- Bureau, 2002. www.census.gov/prod/2002pubs/p60-220.pdf. 15 Schoen C, Doty MM, Collins SR, Holmgren AL. Insured but not ery, a fundamental question remains regarding the role protected: how many adults are underinsured? Health Aff 2005; of primary care in a healthcare system.31 One of the W5289-302. http://content.healthaffairs.org/cgi/reprint/hlthaff. w5.289v1.pdf. current objectives of the UK government is to shift ser- 16 Institute of Medicine. Coverage matters: insurance and health care. vices from hospital based to primary care settings.32 Washington DC: Institute of Medicine, 2001. This raises questions about the appropriate balance 17 Ferris TG, Chang Y, Blumenthal D, Pearson SD. Leaving gatekeeping behind—effects of opening access to specialists for adults in a between services supplied by primary care physicians health maintenance organization. NEnglJMed2001;345:1312-7. and specialists. Comparisons between countries offer 18 Britt H, Miller GC, Knox S, Charles J, Valenti L, Henderson J, et al. General practice activity in Australia 2001-02. Canberra: Australian an opportunity to learn from natural experiments and Institute of Health and Welfare, 2002. www.aihw.gov.au/ may provide insights into how primary care can best publications/gep/gpaa01-02/gpaa01-02.pdf. contribute to equitable, efficient, and effective health- 19 National Ambulatory Medical Care Survey (NAMCS). Atlanta (GA): Centers for Disease Control and Prevention, 2007. www.cdc.gov/ care systems. nchs/about/major/ahcd/namcsdes.htm. 20 Ministry of Health. 2004. Family doctors: methodology and We thank Robin Osborn and her staff at the Commonwealth Fund who description of the activity of private GPs: the national primary medical care survey (NatMedCa): 2001/02. Report 1. Wellington: Ministry of encouraged and believed in the value of this international collaboration, Arpita Health. www.moh.govt.nz/moh.nsf/wpg_Index/Publications-Family Chattopadhyay for her assistance in developing the program for running the +Doctors+NatMedCa+Report+One. bootstrap analysis, and Glenna Auerback for her editorial assistance. We thank 21 Classification Committee of the World Organization of Family Doctors Lisa Valenti for assisting with the analysis of the BEACH data, and Peter Davis, (WICC). ICPC-2: international classification of primary care.2nded. Antony Raymont, Roy Lay-Yee, and the NatMedCa research team for access to Oxford: Oxford University Press, 1998. their data. 22 De Lusignan S. Codes, classifications, terminologies and nomenclatures: definition, development and application in practice. Inform Prim Care 2005;13:65-9. Contributors: All authors contributed to conception, design, analysis, 23 National Center for Health Statistics. International classification of interpretation of data, and drafting and final approval of the article. ABB is diseases, ninth revision, clinical modification. 2007. www.cdc.gov/ guarantor. nchs/about/otheract/icd9/abticd9.htm.

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24 The Johns Hopkins University ACG case-mix system. 2007. www.acg. 29 Stange KC, Zyzanski SJ, Jaen CR, Callahan EJ, Kelly RB, Gillanders WR, jhsph.edu/ResourceCenter.aspx?Type=Documentation. et al. Illuminating the “black box.” A description of 4454 patient visits 25 Efron B, Tibshirani RJ. An introduction to the bootstrap. London: to 138 family physicians. J Fam Pract 1998;46:377-89. Chapman and Hall, 1994. 30 Reinhardt UE, Hussey PS, Anderson GF. Cross-national comparisons 26 Rosenblatt RA, Hart LG, Baldwin LM, Chan L, Schneeweiss R. The of health systems using OECD data, 1999. Health Aff generalist role of specialty physicians: is there a hidden system of 2002;21:169-81. primary care? JAMA 1998;279:1364-70. 31 Bindman AB, Majeed A. Primary care in the United States: organisation of primary care in the United States. BMJ 27 Yarnall KSH, Pollak KI, Ostbye T, Krause KM, Michener JL. Primary 2003;326:631-4. care: is there enough time for prevention? Am J Public Health 32 Department of Health. Our health, our care, our say: a new direction 2003;93:635-41. for community services. London: Department of Health, 2006. www. 28 Ostbye T, Yarnall KSH, Krasue KM, Pollak KI, Gradison M, Michener JL. dh.gov.uk/assetRoot/04/12/74/59/04127459.pdf. Is there time for management of patients with chronic diseases in primary care? Ann Fam Med 2005;3:209-14. Accepted: 9 April 2007

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For the full versions of these articles see bmj.com CLINICAL REVIEW

Acute coronary syndromes without ST segment elevation Ron J G Peters,1 Shamir Mehta,2 Salim Yusuf2

1Department of Cardiology, The diagnosis and management of acute coronary syn- necrosis. Whether myocardial infarction (that is, Academic Medical Center, dromes have been evolving rapidly in recent years. necrosis of cardiac muscle) is present usually becomes PO Box 22660, Amsterdam 1100, New antithrombotic agents have improved the results clear at a later stage, on the basis of laboratory tests Netherlands of medical treatment, and new methods of estimating a (elevation of markers such as creatine kinase MB or 2Department of Medicine, McMaster University and patient’s risk of an adverse outcome help clinicians to cardiac troponins) or on the electrocardiogram (loss Population Health Research decide who may benefit from invasive treatment—that of QRS voltage or development of pathological Q Institute, Hamilton Health is, coronary angiography and subsequent revasculari- waves). Because of the therapeutic decisions that Sciences, Hamilton, ON L8L 2X2, Canada sation (percutaneous coronary intervention or coron- need to be made on admission of patients with acute Correspondence to: R J G Peters ary bypass surgery). As these therapeutic decisions chest pain, before myocardial necrosis may be [email protected] need to be made soon after admission, the classification detected, new terms for the admission diagnosis have

BMJ 2007;334:1265-9 of acute coronary syndromes is now based on the infor- been introduced. These are based primarily on the doi:10.1136/bmj.39220.618646.AE mation that is available on admission. findings on the admission electrocardiogram (table). In the United Kingdom, about 114 000 patients with If ST segment elevation (suggestive of transmural acute coronary syndromes are admitted to hospital ischaemia) is present, a diagnosis of ST segment eleva- each year.1 More than 5.5 million patients present to tion acute coronary syndrome is made. These patients a US emergency department with chest pain and other have an indication for urgent reperfusion treatment, symptoms related to acute coronary syndrome each either by percutaneous coronary intervention or by year.2 Acute coronary syndrome is seen in people of administration of a thrombolytic agent. If no ST seg- all ages, races, and socioeconomic backgrounds. ment elevations are present (normal or depressed ST segments or T wave inversion), a diagnosis of non-ST Pathology segment elevation acute coronary syndrome is made. Acute coronary syndromes generally represent acute If myocardial necrosis is documented, as indicated complications of chronic atherosclerotic disease of the above, a discharge diagnosis of ST segment elevation coronary arteries. The progressive accumulation of myocardial infarction or non-ST segment elevation inflammatory materials and lipids over the years can myocardial infarction is made. According to current ultimately lead to erosions of the intima or rupture of guidelines, any elevation of cardiac markers qualifies lipid rich plaques. Both events are strongly thrombo- as a myocardial infarction.3 Depending on the devel- genic, and a blood clot often forms. Many of these clots opment of the electrocardiogram after admission, remain clinically undetected but contribute to the pro- myocardial infarction may be subclassified as Q wave gressive thickening of the arterial wall and the narrow- or non-Q wave myocardial infarction. If no evidence of ing of the vessel. Thrombi may lead to acute reductions myocardial necrosis exists, a discharge diagnosis of in vessel patency, resulting either in sudden onset or acute coronary syndrome or unstable angina is gener- worsening of angina; they may also acutely occlude ally used. In this review, we focus on non-ST segment the vessel, causing acute myocardial infarction. Inter- elevation acute coronary syndrome. mediate presentations also occur, with incomplete occlusion leading to myocardial damage or, conver- Sources and selection criteria sely, with complete occlusion that does not lead to Acute coronary syndromes represent one of the most necrosis. The last of these may be the case if adequate intensively studied topics in clinical research. Current collaterals have been formed in the preceding weeks or guidelines and practice are based on a very large body months as a response to chronic recurrent ischaemia. of evidence, a summary of which is beyond the scope of this review. Our information came from personal How are acute coronary syndromes classified? archives and searches of Medline with the key words Until recently, the two typical clinical presentations “acute coronary syndrome” and “unstable angina”. were generally referred to as unstable angina and We used current guidelines on the management of acute myocardial infarction. A diagnosis of acute myo- acute coronary syndromes and searched for relevant cardial infarction requires evidence of myocardial Cochrane reviews.

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Classification of discharge diagnoses How can we stratify risk in patients with acute coronary syndrome? Myocardial necrosis ST elevation on The in-hospital management of patients with chest admission ECG Yes No pain is determined by the risk of complications and Yes ST segment elevation myocardial infarction ST segment elevation acute coronary syndrome death. Indicators of high risk include typical com- No Non-ST segment elevation myocardial Non-ST segment elevation acute coronary plaints, documented coronary artery disease, and infarction syndrome advanced age. On physical examination, new mitral Collective terms (Acute) myocardial infarction Acute coronary syndrome or unstable angina regurgitation, hypotension, excessive sweating, pul- ECG=electrocardiogram. monary oedema, and rales are all associated with high risk.6 On the electrocardiogram, new Q waves, new ST segment deviation, or new T wave inversion with How is acute coronary syndrome diagnosed? symptoms indicate high risk. Raised cardiac troponin The main initial diagnostic challenge is to differentiate T, troponin I, or creatine kinase MB in the serum indi- acute coronary syndromes from non-cardiac chest cates myocardial necrosis and a high risk of an adverse pain. The assessment requires a thorough history outcome. In addition, markers of congestive heart fail- (including analysis of risk factors), a physical examina- ure, particularly plasma B-type natriuretic peptide, tion, and, often, an electrocardiogram and determina- have been shown to be independent predictors of tion of serum cardiac “markers” (troponin T, troponin death in patients with non-ST segment elevation I, creatine kinase MB isoenzyme). The most important acute coronary syndrome. determinant is the patient’s history.4 Symptoms of For patients admitted with this diagnosis, several risk acute coronary syndrome include substernal chest scores have been developed from clinical trials and pain, radiating to the arms, the jaw, the neck, the registries.7-10 These can help to identify patients who back, or even the abdomen, which may be accompa- are most likely to benefit from “invasive” treatment nied by nausea, vomiting, dyspnoea, and diaphoresis. (coronary angiography and revascularisation). As Some patients may present without chest pain, and patients included in trials represent a selected group of dyspnoea may be the only complaint.5 Typical chest patients, risk models derived from unselected registries pain that occurs suddenly at rest, particularly in a are probably more reliable in clinical practice (box). young patient, may suggest acute coronary spasm, which is sometimes associated with the use of cocaine How are patients managed in hospital? or methamphetamine. Abnormalities on physical The treatment of patients with non-ST segment eleva- examination are usually absent but may include signs tion acute coronary syndrome, according to current of heart failure, such as rales or oedema, hypotension, guidelines, consists of two components: to alleviate excessive sweating, or new mitral regurgitation. the patient’s complaints of pain and anxiety and to pre- Patients suspected of having acute coronary vent recurrences of ischaemia and progression to (or to syndrome should be referred to a hospital for observa- limit) myocardial infarction.11 12 This requires inten- tion, electrocardiography, and blood testing (cardiac sive antithrombotic treatment, and often an invasive markers). Importantly, a normal electrocardiogram strategy with coronary angiography followed by revas- does not rule out acute coronary syndrome (although it cularisation if appropriate. does make it less likely), particularly if documented after Drug treatment routinely includes β blockers, which relief of symptoms. In addition, normal concentrations reduce myocardial oxygen demand by reducing heart of cardiac markers do not rule out acute coronary rate and blood pressure and reduce the risk of arrhyth- syndrome, particularly if measured shortly after the mias and recurrent ischaemia. Sedatives and analgesics onset of complaints. Elevation of these markers takes may be used with the same goals, by reducing anxiety four to six hours after myocardial necrosis, and six to and pain. Vasodilators, such as nitrates and calcium chan- eight hours are needed before markers of necrosis nel blockers, are used to reduce the dynamic (spastic) appear in peripheral blood. If an initial blood test is component of coronary obstruction, and to lower blood normal, and the history is highly suggestive, most pressure, but none of these drugs has been shown to clinicians do a second test after eight to 12 hours. If this reduce the risk of myocardial infarction or death. is also normal, and the electrocardiogram is normal or shows little acute evolution, then the patient is at very low risk and may be discharged. However, such patients Predictors of death in patients with acute coronary should have an early stress test to document whether syndromes, according to the GRACE registry provoked ischaemia is present. If the cardiac biomarkers Age are raised or the electrocardiogram shows evolutionary Killip class (heart failure) changes, admission to hospital is indicated. Heart rate Imaging techniques may support the diagnostic Blood pressure process by showing wall motion abnormalities (echo- ST deviation on electrocardiogram cardiography, magnetic resonance imaging), ischaemia Cardiac arrest (nuclear perfusion scanning), or coronary pathology Raised creatinine (multislice computed tomography scanning). However, Raised creatine kinase MB or troponin their role has not been firmly established.

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unfractionated heparin or subcutaneous low molecular Tips for non-specialists weight heparins halves the risk of myocardial infarction The likelihood of an acute coronary syndrome should be determined in all patients who or death according to a recent meta-analysis.18 No con- present with chest discomfort (note that angina is rarely chest pain—it is more often a vincing difference in efficacy or safety exists between the tightness or a pressure or a choking sensation) two types of heparin, and no clear differences exist A careful, focused history is the most important diagnostic tool between low molecular weight heparins. Their main Abnormal findings on physical examination are rare in patients with acute coronary advantage is the ease of use, with subcutaneous admin- syndromes istration and no need for laboratory monitoring. Fonda- Unless symptoms are clearly atypical or an alternative diagnosis is probable, initial parinux, a pentasaccharide for subcutaneous use, has assessment should include an electrocardiogram and measurement of cardiac markers recently been compared with enoxaparin, the most Normal findings on the electrocardiogram and normal cardiac plasma markers do not rule out acute coronary syndrome widely studied low molecular weight heparin. A large scale randomised comparison found no difference in the occurrence of death or myocardial infarction in the in-hospital phase.19 However, the risk of bleeding complications was about 50% lower with fondaparinux. In Antithrombotic treatment the subsequent six months, this translated into a signifi- Antiplatelet agents cantly lower mortality. Aspirin is the mainstay of treatment. In an authorita- Bivalirudin is a direct inhibitor of thrombin (that is, tive review by collaborating trialists, the use of aspirin independent of antithrombin III) that has recently been was associated with a nearly 50% reduction in relative compared with combinations of low molecular weight risk of vascular events compared with placebo.13 Addi- heparins or unfractionated heparin with glycoprotein tion of clopidogrel, a platelet membrane ADP receptor 2b/3a receptor inhibitors, in patients with acute coron- antagonist, was studied in a large clinical trial in ary syndromes having percutaneous coronary inter- patients at high risk. It was associated with an addi- vention. The trial results, which have not yet been tional 20% relative risk reduction, with a small increase published, show that bivalirudin alone was as effective in the risk of bleeding (38% increase in relative risk, 1% as either type ofheparin plus a glycoprotein 2b/3a recep- in absolute risk).14 The combination of aspirin and clo- tor inhibitor, but with a lower risk of bleeding. However, pidogrel is now recommended in patients admitted to a bivalirudin was not compared with heparin without gly- coronary care unit with non-ST segment elevation coprotein 2b/3a receptor inhibitors. acute coronary syndrome.11 15 The recommended duration of combined treatment is up to 12 months, Summary of antithrombotic treatment depending on several factors, including the level of Taken together, antithrombotic treatment in patients risk and stent placement. admitted with non-ST segment elevation acute coron- Inhibitors of the platelet glycoprotein 2b/3a recep- ary syndrome should routinely include oral aspirin tor, a third class of antiplatelet agents, have been exten- (daily dose 75-150 mg) and clopidogrel (75 mg daily, sively studied in patients with non-ST segment initial loading dose 300-600 mg). Fondaparinux (at a elevation acute coronary syndrome. In a pooled analy- daily dose of 2.5 mg subcutaneously) is probably the sis, the trials show a modest benefit of glycoprotein 2b/ preferred anticoagulant, although this has not yet been 3a receptor inhibitors (odds ratio 0.91, 95% confidence adopted in guidelines. Alternatively, unfractionated interval 0.84 to 0.98; P=0.015), which seems to be lim- heparin (initial bolus of 60-70 U/kg (maximum 5000 ited to patients who have percutaneous coronary inter- U) and an initial infusion of 12-15 U/kg/h (maximum vention.16 In patients treated non-invasively, the 1000 U/h) to a target activated partial prothrombin benefit is questionable. These studies were not done time of 1.5-2.5 times control value) or low molecular in high risk patients scheduled for percutaneous coron- weight heparins (for example, enoxaparin 1 mg/kg ary intervention, and they were done before routine administration of clopidogrel was introduced. How- ever, a recent well designed randomised study confirmed that abciximab, a glycoprotein 2b/3a receptor Unanswered research questions inhibitor, does provide benefit in patients with non-ST Why do some patients present with unheralded acute segment elevation acute coronary syndrome routinely myocardial infarction and some with unstable angina, managed with an invasive strategy when given in addi- whereas other patients never have acute events in spite tion to aspirin and clopidogrel (relative risk 0.75, 0.58 of chronic coronary artery disease? to 0.97; P=0.03).17 How can we identify patients in whom revascularisation procedures will improve prognosis? Anticoagulants Does a sex difference exist in the balance between risks Four classes of anticoagulants have been tested in and benefits of coronary revascularisation in patients with acute coronary syndromes (as has been suggested patients with non-ST segment elevation acute coronary by some trial results)? syndrome: unfractionated heparin, low molecular In patients who are selected for revascularisation weight heparins, pentasaccharides (inhibitors of factor procedures, is a period of medical stabilisation before X), and direct thrombin inhibitors. On top of aspirin, the intervention beneficial? short term treatment (up to seven days) with intravenous

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SUMMARY POINTS should have coronary angiography followed by revascularisation (if indicated and if possible) or whether this The patient’s history is the most important initial diagnostic tool should be done selectively in patients at high risk or in Patients suspected of having an acute coronary syndrome need to be admitted and evaluated those who are refractory to medical treatment. “ ” by electrocardiography and measurement of cardiac markers Another question that remains unanswered is whether Acute coronary syndromes are classified on the basis of the presence or absence of ST an initial period of stabilisation (“cooling down”) segment elevation on the admission electrocardiogram before proceeding to the catheterisation laboratory is All patients with acute coronary syndromes need intensive medical treatment, including beneficial or whether invasive treatment should be combinations of antithrombotic drugs done as soon as possible. Although this question has In high risk patients, coronary angiography is indicated, with the aim of revascularisation if not been studied in randomised trials, several studies they have suitable coronary anatomy have compared an invasive approach to a more “con- Elevation of cardiac markers determines whether a discharge diagnosis of myocardial servative” approach. In a meta-analysis published in infarction is made 2005, including seven trials and 9212 patients, a rou- After discharge, treatment is aimed at preventing recurrences and treating the underlying tine invasive strategy exceeded a selective invasive atherosclerotic disease process strategy in reducing myocardial infarction, severe angina, and readmission to hospital over a mean follow-up of 17 months.20 Routine intervention was subcutaneously twice a day) may be used. In the associated with a higher early mortality hazard and a OASIS 5 study in patients with acute coronary syn- trend towards a reduction in mortality during longer dromes, a small increase in the incidence of catheter term follow-up. However, a subsequent randomised thrombosis was seen in patients receiving fondapari- study in 1200 high risk patients with non-ST segment nux (0.9% v 0.4%; relative risk 3.59, 1.64 to 7.84; elevation acute coronary syndrome who received opti- P=0.001). If the patient is scheduled for urgent percu- mal medical treatment according to current guidelines taneous coronary intervention, unfractionated heparin found no significant difference in the combined end- may be the preferred anticoagulant. If a patient needs point of death, myocardial infarction, or readmission percutaneous coronary intervention while receiving to hospital at one year follow-up.21 This suggests that if fondaparinux, addition of a small dose of unfraction- medical treatment is optimised, a routine invasive ated heparin is recommended. approach may not be necessary. A recent Cochrane review, including all trials published to date, con- Revascularisation cluded that an invasive strategy in unstable angina/ Debate is ongoing as to whether all patients with non- non-ST segment elevation myocardial infarction ST segment elevation acute coronary syndrome results in a significant 33% relative risk reduction for both the end points of refractory angina and readmission to hospital at six to 12 months.22 However, this ADDITIONAL EDUCATIONAL RESOURCES analysis includes the older trials in which medical treat- Braunwald E, Antman EM, Beasley JW, Califf RM, ment was probably less effective. Cheitlin MD, Hochman JS, et al. ACC/AHA guideline Current guidelines do recommend an invasive strat- update for the management of patients with unstable egy in patients at high risk.11 12 If initially a conservative angina and non-ST-segment elevation myocardial approach is selected—for example, in patients at lower infarction—2002: summary article a report of the risk—the patient should be closely monitored for American College of Cardiology/American Heart recurrent chest pain or signs of ischaemia, using repeat Unstable Angina (Committee on the Management of electrocardiograms, monitoring of the ST segment, Patients With Unstable Angina). Circulation 2002;106:1893-900 and serial measurements of the cardiac markers (creatine kinase MB, troponin). Even in the absence of such Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Management of acute signs, the patient may have significant coronary artery coronary syndromes in patients presenting without disease. Predischarge stress testing is therefore gener- persistent ST-segment elevation. Eur Heart J ally done to determine if the patient is stable and 2002;23:1809-40 whether significant coronary obstructions remain. Resources for patients Alternatively, high risk patients should be considered British Heart Foundation (www.bhf.org.uk/)— for angiography and appropriate revascularisation Information on a healthy lifestyle and explanations of during the initial admission. clinical diagnoses and treatments, plus information on the 300 BHF nurses who provide support, education, What is appropriate long term treatment? and care for heart patients After discharge, management of patients with acute cor- European Society of Cardiology (www.escardio.org/ onary syndromes consists of two main components. — knowledge/links/patients.htm) Information on Firstly, prevention of recurrent ischaemia and death selected heart diseases requires continued treatment with aspirin (indefinitely), American Heart Association (www.americanheart.org) clopidogrel (at least 9-12 months),14 and β blockers. Sec- —Information on a healthy lifestyle and explanations of clinical diagnoses and treatments; includes a “heart ondly, the underlying atherosclerotic process should be 23 24 and stroke encyclopedia” treated by tackling all modifiable risk factors. These includetheroutineuseofastatintolowerplasmalow

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patients presenting without persistent ST-segment elevation. Eur density lipoprotein cholesterol concentrations, use of Heart J 2002;23:1809-40. angiotensin converting enzyme inhibitors,25 strict treat- 13 Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, ment of hypertension and diabetes, cessation of smok- myocardial infarction, and stroke in high risk patients. BMJ ing, achieving an optimal body weight, regular physical 2002;324:71-86. 14 YusufS,ZhaoF,MehtaSR,ChrolaviciusS,TognoniG,FoxKK,etal. exercise, and healthy food choices. Effects of clopidogrel in addition to aspirin patients with acute coronary syndromes without ST-segment elevation. NEnglJMed 2001;345:494-502. Contributors: All authors contributed to the collection of data and to the text 15 Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, of the paper. RJGP produced the first draft and is the guarantor. Hochman JS, et al. ACC/AHA 2002 guideline update for the Competing interests: None declared. management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task 1 Collinson J, Flather MD, Fox KA, Findlay I, Rodrigues E, Dooley P, et al. force on practice guidelines (Committee on the Management of Clinical outcomes, risk stratification and practice patterns of Patients With Unstable Angina). JAmCollCardiol2002;40:1366-74. unstable angina and myocardial infarction without ST elevation: 16 BoersmaE,HarringtonRA,MoliternoDJ,WhiteH,TherouxP,Vande prospective registry of acute ischaemic syndromes in the UK (PRAIS- Werf F, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary – UK). Eur Heart J 2000;21:1450 7. syndromes: a meta analysis of all major randomised clinical trials. 2 McCaig LF, Burt CW. National hospital ambulatory medical care Lancet 2002;359:189-98. survey: 2002 emergency department summary. Advance Data from 17 Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, et al. Vital and Health Statistics 2004;(340). Abciximab in patients with acute coronary syndromes undergoing 3 ApertJS,ThygesenK,AntmanE,BassandJP.Myocardialinfarction percutaneous coronary intervention after clopidogrel pre-treatment: — redefined a consensus document of the Joint European Society of the ISAR-REACT 2 randomized trial. JAMA 2006;295:1531-8. Cardiology/American College of Cardiology Committee for the 18 Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusuf S. redefinition of myocardial infarction. JAmCollCardiol Unfractionated heparin and low-molecular-weight heparin in acute 2000;36:959-69. coronary syndrome without ST elevation: a meta-analysis. Lancet 4 Diamond GA, Forrester JS. Analysis of probability as an aid in the 2000;355:1936-42. clinical diagnosis of coronary-artery disease. NEnglJMed 19 YusufS,MehtaSR,ChrolaviciusS,AfzalR,PogueJ,GrangerCB,etal. 1979;300:1350-8. Comparison of fondaparinux and enoxaparin in acute coronary 5 McCarthy BD, Wong JB, Selker HP. Detecting acute cardiac ischemia syndromes. NEnglJMed2006;354:1464-76. in the emergency department: a review of the literature. JGenIntern 20 Mehta SR, Cannon CP, Fox KA, Wallentin L, Boden WE, Spacek R, Med 1990;5:365-73. et al. Routine vs selective invasive strategies in patients with acute 6 Goodacre S, Locker T, Morris F, Campbell S. How useful are clinical coronary syndromes: a collaborative meta-analysis of randomized features in the diagnosis of acute, undifferentiated chest pain? Acad trials. JAMA 2005;293:2908-17. Emerg Med 2002;9:203-8. 21 De Winter RJ, Windhausen F, Cornel JH, Dunselman PH, Janus CL, 7 AntmanEM,CohenM,BerninkPJ,McCabeCH,HoracekT, Bendermacher PE, et al. Early invasive versus selectively invasive Papuchis G, et al. The TIMI risk score for unstable angina/non-ST management for acute coronary syndromes. NEnglJMed elevation MI: a method for prognostication and therapeutic decision 2005;353:1095-104. making. JAMA 2000;284:835-42. 22 HoenigMR,DoustJA,AroneyCN,ScottIA.Earlyinvasiveversus 8 Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee KL, conservative strategies for unstable angina and non-ST-elevation et al. Predictors of outcome in patients with acute coronary myocardial infarction in the stent era. Cochrane Database Syst Rev syndromes without persistent ST-segment elevation: results from an 2006;(3):CD004815. international trial of 9461 patients. Circulation 2000;101:2557-67. 23 European guidelines on cardiovascular disease prevention in clinical 9 Jacobs DR Jr, Kroenke C, Crow R, Deshpande M, Gu DF, Gatewood L, practice: third joint task force of the European and other societies on et al. PREDICT: a simple risk score for clinical severity and long-term cardiovascular disease prevention in clinical practice. Eur J prognosis after hospitalization for acute myocardial infarction or Cardiovasc Prev Rehab 2003;10(suppl 1):S1-78. unstable angina: the Minnesota heart survey. Circulation 24 Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, et al. 1999;100:599-607. AHA/ACC guidelines for secondary prevention for patients with 10 Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F, coronary and other atherosclerotic vascular disease: 2006 update: et al. A validated prediction model for all forms of acute coronary endorsed by the National Heart, Lung, and Blood Institute. syndrome. JAMA 2004;291:2727-33. Circulation 2006;113:2363-72. 11 Gibler WB, Cannon CP, Blomkalns AL, Char DM, Drew BJ, 25 Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin- Hollander JE, et al. Practical implementation of the guidelines for converting-enzyme inhibitors in stable vascular disease without left unstable angina/non-ST-segment elevation myocardial infarction in ventricular systolic dysfunction or heart failure: a combined analysis the emergency department. Circulation 2005;111:2699-710. of three trials. Lancet 2006;368:581-8. 12 Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Management of acute coronary syndromes in Accepted: 23 April 2007

CORRECTIONS AND CLARIFICATIONS Minerva Obituary: Arthur Hamilton Crisp We misspelt the second name of one of the authors of the Professor Arthur Hamilton Crisp died from kidney picture item in a recent Minerva (BMJ 2007;334:908, 28 cancer, and not from stomach cancer as was stated Apr, doi: 10.1136/bmj.39190.509190.BD). in this obituary by Caroline Richmond Madanagopalan Ethunandan (not Ethundandan) is the (BMJ 2007;334:540, 10 Mar, doi: 10.1136/ correct spelling. bmj.39125.617153.FA).

ABC of Clinical Electrocardiography: Conditions not Obituary: John Cosh primarily affecting the heart In this obituary of John Cosh by Caroline Richmond Here’s a correction referring back to 2002. A caption (BMJ 2005;331:1026, doi: 10.1136/ was wrong in this article by Corey Slovis and bmj.331.7523.1026) it has emerged two years later Richard Jenkins (BMJ 2002;324:1320-3, doi: 10.1136/ that we should not have stated that a manufacturer bmj.324.7349. 1320). In the section “Other non-cardiac of herbal medicines, Gerard House, later became conditions” the caption to the first figure should Bio-Health Ltd. In fact, we understand that it was have read: “Short QT interval in patient with David V Smith who founded Bio-Health, in hypercalcaemia [not hypocalcaemia] (calcium 1981, and then sold shares to new directors in concentration 4 mmol/l).” 1996.

BMJ | 16 JUNE 2007 | VOLUME 334 1269 PRACTICE For the full versions of these articles see bmj.com

A patient’s journey Cystic fibrosis

Emma Wicks

Editorial by Wallis As the Good Witch told Dorothy in the Wizard of Oz: Companions on the journey Cystic Fibrosis Trust, Bromley, Kent it is always best to start at the beginning. Growing up, While still a teenager I told my parents, “I’m old BR1 1B I always knew that I had cystic fibrosis, the same way enough to take care of myself.” What rubbish. Nobody, [email protected] I knew I had blue eyes and my cousins could all run whatever their age or health status, is past needing a faster than me. bit of help. As I become sicker it will be my loved ones BMJ 2007;334:1270-71 I was lucky enough—though my parents did not think taking care of me once again. I know I will have to rely doi:10.1136/bmj.39188.741944.47 so at the time—to be diagnosed at two days old. The more on their support in the future. I am not sure who Contributors: EW wrote the main right information at diagnosis is crucial. After being told is looking forward to it the least. article, and KL supplied the box. their daughter had a disease whose name they could Although I do not always want it to be, cystic fibrosis Competing interests: None not spell, and with no information from the hospital, is a huge part of my life and of the lives of those close declared. my parents found out about it for themselves. Parents to me. It is important that healthcare professionals do Provenance and peer review: Not commissioned; not peer reviewed. nowadays might use the internet; mine went to the not forget the people close to me; the relationship pro- Accepted: 27 March 2007 library. The book they found, printed 15 years earlier, fessionals have with their patients should extend to the told them to abandon all hope and not become too people who care for them every day. My companions attached to me. resent my illness more than I, because I have control over it while they look on helplessly, and some may Travelling alone need additional support. The road travelled with cystic fibrosis is often deserted, It can be hard on my fiancé, as he feels responsi- devoid of like minded companions. Growing up, some ble for my wellbeing and compliance with treatment. children picked on me because of my cystic fibrosis, Moreover, he is still learning, as we all are. He has but most of my classmates were too busy learning how many questions, some of which seem a bit stupid, but it to do chest physiotherapy or fighting over the honour is important that members of the cystic fibrosis team do of keeping me company when I was too unwell to go not make him feel the questions are unimportant. out at playtime. I decided that those who were mean were simply jealous of my “special treatment.” If only What adults with cystic fibrosis need they had known that I would gladly have swapped with A good relationship with healthcare professionals is them in an instant. essential, as they eventually become part of a patient’s Today, I welcome and respect the practice of segrega- extended family. People with long term conditions tion to prevent cross infection. Technology has lessened need people with whom they can discuss their con- the impact of infection, but the condition is still not easy cerns, beyond the medical ones. I am lucky; I attend a to bear. I wish I could sit in a room of people who know specialist centre where every member of staff is dedi- what it is to live with it. cated to looking after people with cystic fibrosis. I know many people with cystic fibrosis, although It is important that health professionals should see none of them are close friends. This is a choice I have the person with cystic fibrosis as part of the team, made. The close friends with cystic fibrosis that I had their views being as important as professionals’ own. previously have all died. Having friends who have cystic I become frustrated when clinicians seem unable to fibrosis can become a burden. I know I have this disease accept that I, having lived with cystic fibrosis for more and I live with it every day, but to have it staring back at than 20 years, might know more about my illness than me through the eyes of another can be daunting. they do. Health professionals may be experts in their There are the bad days—the ones where I have to field, but patients are experts in their lives. The best ask for a helping hand, when I cannot be independent, doctor-patient relationships are those in which both when people I love have to clear up vomit and faeces parties educate each other. and change their plans around me. Although they prob- Patients need access to information about cystic ably do not see me as a burden, that is how I feel. It fibrosis. If professionals do not provide the right infor- is a bizarre situation; having this disease has made me mation at the right time, patients will go and look for grow up faster, yet because I am ill I am still heavily themselves. Plenty of good quality information is avail- dependent on others. able, but there is just as much incorrect information,

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Useful resources too, especially on the internet. Patients need to be able minutes, including cleaning the equipment. The new to filter out misleading facts, or have access to people nebulisers are compact enough not to need a separate The Cystic Fibrosis Trust who can guide them. suitcase for taking them on holidays. The physiothera- (UK)—telephone: +44 (0) 20 8464 7211; www. pists now supply patients with a range of gadgets to cftrust.org.uk Losing the path clear the chest of mucus. It may not take less time to The Cystic Fibrosis Having cystic fibrosis is different for everyone. Even do, but it is much more pleasant than chest percus- Foundation (USA)—toll with specialist multidisciplinary care it is still possible sion—and I can do it by myself, so nobody has to find free telephone: +1 800 to lose grip of the steering wheel and veer off course. time to help me. FIGHT CF (344-4823); For example, when I have an acute infection I would The best news is that people with cystic fibrosis are www.cff.org love to take my intravenous antibiotics at home. It living their lives, and living them longer. We have jobs, The Breathing Room—A is much better than sitting in hospital for two weeks, families, and children. Most of us are going out and virtual community of especially when it is too far for anyone to visit. During doing things our peers would never dream of doing. adults with cystic fibrosis, my childhood my local hospital sent me home, armed sharing experiences with 15 minutes’ worth of training and one nervous The bad news with both informal and professional caregivers; mother, because they needed the bed. It was a disaster; Of course, not everything is as it could be. Everyone www.thebreathingroom. we managed only three days, and the experience has with cystic fibrosis in the United Kingdom does not org stopped me from attempting intravenous treatment at receive safe and appropriate care from a specialist home. I am probably capable, but as I live outside multidisciplinary team. Because adults are not auto- the hospital catchment area for homecare nursing I matically entitled to free prescriptions, I spend a for- would have no support. With proper training, sufficient tune paying for drugs—when I can get them in the first supplies, and adequate support I am sure I would feel place. My general practitioner is fantastic, but sadly differently. “postcode prescribing” is as prevalent as ever, and I would have given anything to attend a transition across the country, people living with cystic fibrosis clinic when I was 16. Instead, I received a letter stating are fighting battles with primary care trusts. that my next appointment would be in an adult clinic at another hospital. Now, people with an up to date Journey’s end atlas of knowledge patrol the rocky roads of Transition. My biggest fear is the future; it is difficult to know Although this is far from perfect, it is good to know that what it will bring. It is difficult to plan for the time that certain things are improving. my parents were told I would not have. It is hard to think about getting a mortgage, or starting a pension The good news when you’re not sure you’ll live long enough to have Mostly, the future is bright. Gene therapy, while not a retirement. exactly just round the corner, is looking extremely But I do not sit worrying about when I’m going to likely and is an incentive to adhere to treatments. The die. I think about it, but do not walk around clutching healthier patients’ lungs are, the more likely they will my funeral arrangements. be able to benefit from the therapy. So, I will worry about the future when it arrives. The treatments themselves have become less cum- Until then, there are too many things to live for— bersome. Carrying out my nebulised treatments used my wedding, books to read, and bands I still have to take an hour of my day; now it takes around 30 to discover.

A RESEARCHER’S PERSPECTIVE Identification of the cystic fibrosis gene in 1989 has led to earlier, more whether to have families of their own. Transition clinics, staffed by a accurate diagnosis, and neonatal screening is being rolled out throughout multidisciplinary team, have been established to enable a smoother journey the UK. Better understanding of the condition has ensured progressively between paediatric and adult care, although resources are not always more effective, patient friendly, treatment and care, most of which is carried available to provide the holistic care that these young adults need. Despite out at least daily by family members in the home. requiring daily, life sustaining treatment, most adults with cystic fibrosis Many young people around Emma’s age decide against befriending others continue to pay prescription charges. with cystic fibrosis, and this may result in a feeling of isolation. In 1996, The possibility of a lung or heart-lung transplant is a hope shared by many the Cystic Fibrosis Trust began to fund expert patient advisers, contactable with end stage cystic fibrosis, yet fewer than half of those on the waiting list through the trust, whose role is to enable all those affected by cystic fibrosis will live long enough to receive donor organs. Of those who do, fewer than to have a voice in service planning, delivery, and review. half will survive for 10 years or more. End of life care for this population is Average survival age for those with cystic fibrosis, currently 31 years, is variable; currently many young people die in their teens, without access to a expected to reach 50 years for those born at the turn of the 21st century. For dedicated supportive or palliative care service. Emma is typical of the scores the first time in history, adults with cystic fibrosis in Britain will outnumber of young people and families affected by cystic fibrosis that I have worked children living with the disease. As individuals age and their health declines, with in research projects over the past 10 years. Although they face adversity many conditions related to cystic fibrosis, such as diabetes, osteoporosis, almost daily, an attitude of “life is short; live it to the full” prevails. Excellent and liver disease, become more likely. progress has been made in helping these young people to fight this disease, Living into adulthood also presents those affected with new psychosocial but there is still much more to be done challenges: taking over responsibility for their treatment and care; negotiating further education, employment, and finances; gaining greater Karen Lowton senior lecturer in ageing and health, Institute of Gerontology, King’s College independence from parents; managing personal relationships; and deciding London, London WC2R 2LS

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Change page Established corticosteroid creams should be applied only once daily in patients with atopic eczema

Hywel C Williams

The clinical problem KEY POINTS Centre of Evidence Based Atopic eczema affects many adults and up to 20% of Dermatology, Queen’s Medical 1 2 • Established topical corticosteroids such as Centre, University of Nottingham children, with health costs comparable to diabetes 3 NG7 2UH and asthma. One community survey of 1760 young betamethasone valerate have typically been used twice hywel.williams@nottingham. children in the United Kingdom found that 84% had daily or more frequently for treating inflammatory episodes ac.uk mild eczema, 14% moderate, and 2% severe eczema.4 of eczema

BMJ 2007;334:1272 Topical corticosteroids are a mainstay of treatment • Reducing the frequency of application to once daily does doi:10.1136/bmj.39195.636319.80 for inflammatory episodes.5 Most long established not seem to result in loss of efficacy and could lead to fewer . topical corticosteroids such as betamethasone valer- local side effects ate or hydrocortisone are applied at least twice daily, • Using topical corticosteroids just once a day may be more but three newer preparations (mometasone, fluti- convenient for patients and may save costs if established casone, and methylprednisolone) have been devel- preparations are used oped for once daily application. Here, I propose that established preparations need be applied only once methasone with once daily newer preparations. A daily. blanket recommendation for a switch to once daily application of topical corticosteroids could paradoxi- The evidence for change cally increase costs.6 This dilemma led to a mixed Ten randomised controlled trials compared once recommendation in the original NICE guidance to daily versus more frequent application of topical use topical corticosteroids once or twice daily and to corticosteroids within the same potency group. The use the cheapest alternative.7 Later papers have been findings are summarised in a UK Health Technology more forthright in supporting once daily application Assessment report and guidance from the National of established corticosteroids.12 13 Institute for Health and Clinical Excellence (NICE).6 7 Another short term study has been published more The barriers to change recently.8 None of the studies found clear evidence The case for changing to once daily application of that applying topical corticosteroids more than once established corticosteroids is strong. It is based on a day produced better overall clinical outcomes in lack of evidence of superior efficacy in 11 randomised eczema, such as the number of people with a good controlled trials; cost savings of up to 50% to the state response. Clear evidence of a faster response with or patient if an established preparation such as beta- more frequent use or a better response in subgroups methasone valerate 0.1% is considered; the conven- such as children was lacking. No data were given on ience to patients of applying preparations just once relapse rates. daily (important as a recent study suggested that mean The main adverse effect of topical corticosteroids adherence to twice daily topical corticosteroids was is thinning of the skin.9 The studies included in the only 23%14); and the possibility that side effects such technology assessment were too short in duration as skin thinning ca n be reduced. Conflicting written Change Page aims to alert (three to four weeks) to see if once daily application advice in package inserts can be overcome by coun- clinicians to the immediate results in less skin thinning. However, as skin thin- selling patients beforehand. A change to once daily need for a change in practice to 15 make it consistent with current ning is related to the amount and duration of topical topical corticosteroids was suggested 10 years ago. evidence. The change must corticosteroid, its strength, and its site of application,10 Perhaps the biggest barrier to change is habit. be implementable and must reducing the frequency of application could reduce offer therapeutic or diagnostic advantage for a reasonably local adverse effects. How should we change our practice? common clinical problem. It seems logical that applying topical corticoster- Patients using moderate, potent, or very potent topical Compelling and robust evidence oids once daily instead of twice daily would reduce corticosteroids more than once a day should switch to must underpin the proposal for change. costs by up to 50%. However, three newer potent once daily use. However, the above evidence on short Series editor: Joe Collier topical corticosteroid preparations have been spe- term use of mostly potent topical corticosteroids in ([email protected]), cifically manufactured and tested for once daily use people in secondary care may not be generalisable to professor of medicines policy, St George’s Hospital and (mometasone furoate, fluticasone propionate, and those with very mild eczema using mild preparations, Medical School, London. methylprednisolone aceponate7 11). Newer once daily such as 1% hydrocortisone, for longer periods. Anyone wishing to propose preparations may still cost more than twice daily use a change in clinical practice should discuss the proposal of older preparations such as betamethasone valer- Competing interests: None declared. with Joe Collier at an early stage ate. No trial has directly compared once daily beta- A full version of this article and the references are on bmj.com

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10-minute consultation Chronic kidney disease

Prabir Kumar Mitra,1 Peter R W Tasker, 1 M S Ell 2

A 68 year old man sees you after you sent him a letter What you should do 1 Queen Elizabeth Hospital, saying that the results of blood tests done over the past • Ask about symptoms of cardiovascular King’s Lynn, Norfolk PE30 4ET year to monitor hypertension show that he has chronic diseases (such as breathlessness, pedal oedema, 2 St James’ Medical Practice, kidney disease (CKD). He is worried, as he thought that chest pain, claudication), lower urinary tract King’s Lynn high blood pressure was his only medical problem. symptoms, and compliance with antihypertensive Correspondence to: P K Mitra treatment. [email protected] What issues you should cover • Most patients are asymptomatic, but note any • Explain the terms CKD and estimated glomerular symptoms suggestive of underlying systemic BMJ 2007;334:1273 doi: 10.1136/bmj.39196.714491.94 filtration rate (eGFR). To most patients “kidney diseases such as vasculitis, lupus, or myeloma. . disease” means dialysis and shortened life • Ask about cardiovascular risk factors: smoking PKM planned and wrote the main expectancy. Explain that CKD is a spectrum of status, alcohol consumption, diet, and treatment draft and oversaw submission. disease, with mild renal impairment at one end he is taking, including over the counter drugs MSE is the guarantor. MSE and PRWT helped revise the and established renal failure at the other, and that (especially non-steroidal anti-inflammatory manuscript. eGFR, a number that is based on the “modification drugs). Ask about family history of diabetes, of diet in renal disease” formula, determines the cardiovascular disease, hypertension, peripheral From the archive: For more about stage of CKD. vascular disease, and polycystic kidney disease. estimation of glomerular filtration rate see Giles and Fitzmaurice BMJ • Reassure him that CKD is common (affecting • Calculate his serial eGFRs. 207:334:1198-1200 5-10% of the population, this percentage rising • Record his blood pressure and weight and among people aged >70 years). Most people analyse his urine (and culture the sample if the remain well and do not progress to established results for nitrites and leucocytes are positive). renal failure but have a higher than normal risk of Assess his fluid status and examine his abdomen developing cardiovascular disease. Hypertension is for enlarged kidneys or bladder. associated with silent development of CKD. Timely • Management will vary according to the stage of identification and optimal management of CKD, CKD—see box. including well controlled blood pressure, have been • Offer him a further consultation to discuss any shown to retard its progression. Explain that serial unanswered questions and concerns. Arrange measurement of eGFR will allow you to judge nutritional support if it is needed, and give This is part of a series of whether his condition is progressing and at what lifestyle advice. Refer him to a nephrologist if occasional articles on common rate. this is indicated by the UK CKD guidelines (see problems in primary care. • Explain that your aims are to ascertain whether Useful resources box). The BMJ welcomes contributions from general practitioners to the there is a correctable cause for the biochemical The full version of this article containing a table describing the stages of series findings and to limit any damage to his kidneys. chronic kidney disease is on on bmj.com

Useful resources Managing chronic kidney disease Department of Health. The • Stage 1 or 2, and stage 3 with stable function (change in eGFR of <2 ml/min/1.73 m2 over six or more months): monitor renal national service framework function annually. In cases of progressive stage 3 disease (change in eGFR of >2 ml/min/1.73 m2) monitor six monthly. for renal services. Part two: • Stage 3: check haemoglobin, potassium, calcium, phosphate, and parathormone concentrations (follow local protocol chronic kidney disease, for parathormone monitoring), and request renal ultrasonography if he has lower urinary tract symptoms, refractory acute renal failure and end hypertension, or an unexplained progressive fall in his eGFR. of life care. www.dh.gov. uk/publications • Stage 4 or 5: refer to secondary care. Joint Specialty Committee • If proteinuria is detected (from an early morning sample), check his urine protein:creatinine ratio and refer him to a on Renal Medicine of the nephrologist if the concentration is persistently >100 mg/mmol. Royal College of Physicians • In the case of a rapidly worsening creatinine concentration (an increase of >50%) or eGFR (a reduction of >25%), ensure of London and the Renal that reversible causes have been excluded. A rise of serum creatinine by 20% or fall of eGFR by 15% as an apparent Association. Chronic kidney consequence of use of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) may be due disease in adults: UK to atherosclerotic renal artery stenosis, requiring immediate discontinuation of the drug and referral to a nephrologist. guidelines for identification, • The threshold blood pressure for starting antihypertensive treatment with an ACEI or ARB should be 140/90 mm Hg. Aim for management and referral. a pressure of <130/80 mm Hg (125/75 mm Hg if proteinuria is present). www.renal.org/CKDguide/ • For patients with a 10 year risk of cardiovascular disease of >20% (according to the Joint British Societies’ guidelines on full/CKDprintedfullguide.pdf prevention of cardiovascular disease in clinical practice (Heart 2005;91(suppl 5):v1-52)), consider treatment with lipid Renal Association’s eGFR lowering drugs and aspirin—provided that his blood pressure is <150/90 mm Hg. calculator. www.renal.org/ eGFRcalc/GFR.pl • Stop use of any nephrotoxic drug.

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Communication: the forgotten palliative care emergency PERSONAL VIEW Mark Pickering, Rob George

67 year old man was transferred located the nurse consultant, to our hospice from the local who was known and trusted district general hospital. He had by the family. The patient’s end stage cardiac failure, and wife would not consider an implantable cardioverter deactivation without speaking Adefibrillator was in place. The referral was to her, but a brief conversation clear: he was coming to die. Just as clear was between the two assured her the fact that he didn’t know his prognosis that this was the appropriate but was apparently expecting rehabilitation. thing to do. It was too near the By the time I (MP) had admitted him he weekend to undertake the usual had turned blue three times, and during one full deactivation, but a suitable magnet was emergency. At the end of of these cyanotic attacks the defibrillator had sent by courier that evening for use by the our meeting his wife presented us with discharged. It was clear he was near the end. nurses in an emergency. the Christmas present she had bought for As I began to explore his understanding of This done, it was time to talk to the her husband before his death—an ornament the illness and what the future held for him, patient. As we discussed his prognosis, he that now stands in the hospice as a memorial I felt a subtle squeeze on my elbow from his turned his eyes up to mine and said, “I to the short time he spent with us. wife, as much as to say, “Don’t tell him he’s thought as much, doc.” He had suspected for Many have written on the importance dying.” It was 4 30 on a Friday afternoon, a while that he was near the end but needed of recognising and treating emergencies and this had all the makings of a bad death. it confirmed by someone in authority before in palliative care and oncology. Likewise, This was obviously a communication he would discuss it openly. In a constructive much has been published on the importance emergency. Certain things had to be conversation we discussed symptom control, of communication in palliative care. But the communicated clearly in a short period of explored some spiritual issues, and agreed two concepts have rarely been explicitly time in order to prevent his death being on the need to speak openly with his wife linked, with communication identified as a a complete mess for him and his family. and family. By now it was after 5 pm and I genuine palliative care emergency. Although The first priority was to speak with his wife was booked on a train to get to a wedding in practice we often recognise what needs and daughter. Both were fully aware of the at the other end of the country. I left hoping to be done in a particular situation, formally prognosis but adamant that he should not be that the patient and his family would take identifying communication emergencies as told, as “he couldn’t cope with it.” He had the opportunity to talk. one of the main emergencies in palliative always been the strong one who protected On returning the following Tuesday I care would increase awareness and improve the rest of the family. learnt that he had indeed required sedation their management. I explained that we had an opportunity with a syringe driver on the Saturday The consequences of misdiagnosing or that many people miss—to say the things and had died peacefully on Sunday. That failing to treat a communication emergency that needed to be lunchtime the family was due to attend for a can be important. For patients themselves A looming bad said, to “put the bereavement meeting and collect the death it could result in a difficult death, where death had been house in order” and certificate. I wondered how they would look existential distress may simply be labelled as transformed into say goodbyes. If this back on that last Friday evening they had terminal agitation, leading to greater levels a good one wasn’t taken, they spent with the man they all loved. of sedation. For relatives it could result in might regret for years Although clearly sad at his death, years of avoidable guilt, regret, and sadness. that the parting was sudden and messy. they were deeply grateful for the frank This will most certainly make the normal They concurred, and we agreed that I discussions we had had. After I left grieving process more difficult. should speak to him alone. on Friday they had spent the evening Palliative care professionals particularly Another urgent priority was to deactivate together saying goodbyes, agreeing funeral (but also other healthcare professionals) the defibrillator. This had not been arrangements, even enjoying a laugh and a should be as alert to communication discussed, but the last thing I wanted was for joke together as a family. What a difference emergencies as to any of the more physical a dying man to be repeatedly flogged back from the cloak of secrecy that had prevailed ones. The consequences of missing them can to life when his body was begging to be left on his arrival! I could not have imagined be just as serious. alone, causing unnecessary distress to patient a better result—a looming bad death had Mark Pickering is senior house officer and Rob George and relatives. I called the teaching hospital been transformed into a good one by the is locum consultant, Lions Hospice, Gravesend, Kent that had implanted his defibrillator and diagnosis and treatment of a communication [email protected]

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The “striped (and sometimes flashy)” sandwich of supinator containing the posterior interosseous nerve is “thin, so do not nick the nerve.”

How not to make a mess during extensile exposure, p 1277 review of the week Fractured: picking up the pieces

An author’s fractured arm led to a book on the intrusive surveillance of doctors, finds Jessica Watson

“Medicine can, and does, save lives and contribute to Disappointed by mainstream medicine, Oakley also wellbeing, but much of it is a massive cultural deceit.” turns to acupuncture, and its more holistic approach This is the controversial conclusion Ann Oakley makes her hand “feel a little bit more like part of me reaches after being treated for the fracture of her right again.” A fundamental difference between Western arm. Increasingly the medical profession is becoming medicine and acupuncture, she argues, is the insepa- aware of the value of patients’ narratives, yet Ann rability of mind and body, and this theme of embodi- Oakley is no ordinary patient. As professor of sociol- ment is central in the book. ogy and social policy at the Institute of Education, Within this theme Oakley explores several other University of London, she treats her experiences as a areas, with some controversial conclusions. Screening “field trip into the land of bodily damage, disability, “isn’t to prevent disease, but to change identities—to and personal injury litigation.” In an attempt to make produce patients.” To back this up she says that evi- sense of her experiences she launches a huge research dence to support the benefits of screening is minimal, project that touches on a myriad themes including yet screening subjects large numbers of women to limitations of Western medicine, medical litigation, unnecessary investigations and anxiety. the problem of ageing, disability, and the confusion She feels that ageing women are excessively medi- Fracture: Adventures of between bodies and identity. calised and medicated, with hormone replacement a Broken Body Oakley portrays doctors as self serving and insular. therapy being “the ultimate case study in pharmaceu- Ann Oakley One recurring theme is a lack of communication and tical marketing, in how to make millions by invent- Policy Press, £12.99, pp in particular an inability or unwillingness to listen: ing new conditions that need treatment, playing on 186 “It quickly becomes clear that what worries me is not people’s susceptibilities, and ignoring the bad news ISBN 978 1 86134 937 8 what worries the doctors,” she writes. The doctors in about what drugs do to the body.” Also, one chapter Rating: her case were interested in the problems they saw—the is devoted to a damning criticism of the American **** state of the scar, the movement of the arm, and the system of litigation, blame culture, and lawyers as degree of pain. No one took the time to find out what “ambulance chasers.” Ann Oakley’s concerns were, largely that her hand This is a surprisingly readable book, given the com- felt like “an alien object”: “I don’t feel I have a right plexity of some of the issues discussed. It interweaves hand. It just hangs there at the end of my arm. I hate the author’s own experiences with other patients’ sto- it.” She is not only right handed but a writer of sociol- ries and evidence from research. Some of Ann Oak- ogy books and novels, and devotes a whole chapter ley’s statements seem to overdramatise the facts to to exploring the personal, cultural, and psychological court controversy, but the book has some interesting significance of the right hand. lessons for doctors. The medical model of Western medicine, or “body Although patient centredness, communication as machine” approach, “distorts the human experi- skills, and the holistic approach are increasingly being ence of living in a body,” Oakley argues. In this model incorporated into medical teaching, this book finds a The doctors in “objective,” quantitative tests are seen as providing gap between the theory and practice of these skills. Oakley’s case were the answers, and in the process the patient’s subjec- It would be easy to dismiss the concerns raised as interested in the tive experience is ignored and delegitimised. Nerve the anecdotal experiences of one patient, but many problems they conduction studies are an example of “the mechanical doctors will recognise an uncomfortable reflection of saw—the state model of the body par excellence; the patient doesn’t some aspects of medical practice. Whether the doctors of the scar, the have to speak, or even, really, be conscious at all.” did a technically good job in the medical task of fix- movement of the On the basis of these “objective” tests, doctors dis- ing broken bones was, to this patient, secondary. Her arm, and the degree charged Oakley as “cured”— even though “these tests book reminds us all of the importance of listening to said nothing about sensibility—about what I felt.” and learning from our patients and encourages reflec- of pain. No one took Oakley portrays her physiotherapist in a much tion on the universal experience of living in a body. the time to find out better light than the doctors: “the difference is that Jessica Watson is academic FY2 doctor, United Bristol Healthcare what her concerns Theresa listens when I tell her; she isn’t a machine.” Trust and University of Bristol [email protected] were

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110%

FROM THE I am going to give this 110%. Sporting analogies are ening and distorted version of “We are the Champions,” FRONTLINE everywhere, for sport is a microcosm of life itself. Sport drowning out any dissent. All attempts to export this incorporates important themes like the team over the sport, perhaps not unsurprisingly, have failed. Des Spence individual, obeying rules, the threat of sanctions, per- But the traditional model of the NHS is one of a sistence, endurance, pride, effort, structure, hierarchy, soccer match in a dog fouled city park. The nurses are and—all important—the need to meet defeat and victory the defence: solid, dependable, organised, and quietly with equal measure. Perhaps these crude analogies are getting on. The GPs are the midfield: holding the ball, legitimate and we should view the NHS as just another playing it around and holding the possession, helping in big team game. defence but sometimes going forward. The consultants Let’s work this sporting analogy further. The NHS are the two fiery glory hunters up front, aggressively is at risk of becoming American football: teams within seeking to score that all important diagnosis. teams, producing reams of meaningless statistics; con- So you can stuff staying up half the night for the medi- stantly changing shifts of players; superspecialised play- cal superbowl party. Give me my NHS football world ers performing one single task; start-stop, clock watching, cup, a truly global event with poverty no barrier to suc- pointlessly technological; glitzy, covered in layers of pad- cess—an event where a truly gifted individual can make ding, pumped up on growth enhancers with unknown a big difference and raise the morale of a whole nation. long term consequences—even the gleam of the pitch is There is the odd shouting match, but these get “sorted” utterly synthetic. Just expensive and complicated, but in the pub afterwards. It is the NHS’s complete simplic- worse still: interminable and dull. Our population of ity that makes it so beautiful and highly regarded. Had health spectators, now obese, gazes on, chomping on enough? I’ve done my best and you can’t ask more than foot-long hotdogs as they guzzle down their gallons of that. fizzy drinks. The announcement system blasts out a deaf- Des Spence is a general practitioner, Glasgow [email protected]

Jobs for the boys PAST CARING Climbing the medical career ladder prevailing medical ignorance this amputate a leg from the wrong Wendy Moore used to be so much simpler. Before need not be overly long. direction, leaving a generous flap the advent of tedious form-filling, And naturally the system proved of skin on the discarded limb and maddening technical hitches, and unpopular with anyone lacking a protruding bone on the stump, the rush for too few posts, obtaining appropriate blood ties. Devoid even the amiable South conceded a plum job for life was governed of illustrious ancestors, surgical that his operations were “generally by an application system everyone apprentice John Flint South very badly performed, and could understand: nepotism. gamely accepted the appointments accompanied with much bungling.” For centuries, all that was needed procedure at St Thomas’ when Ultimately the system became for an aspiring trainee physician the death of his tutor Henry Cline discredited under intense media or surgeon to secure a lucrative created a vacancy in 1820. “Several scrutiny. Lancet editor Thomas countryside practice or a top post of the other hospital apprentices Wakley crowned a sustained at an eminent teaching hospital was sent in their humble petitions to campaign against nepotism with the right family connections. In a the Governors to be chosen their a dazzling exposé in 1828 of spirit of continuity only equalled surgeon, I among the number,” he a fatal operation to remove a by The Forsyte Saga, medical wrote, “but it was a mere matter of bladder stone by Bransby Cooper, dynasties ruled supreme. While the form.” Cline’s cousin, Joseph Henry inept nephew of the esteemed Chamberlens kept their midwifery Green, was duly elected to the job. Astley Cooper, at Guy’s. Despite practice in the family for five With no recognition of merit, Bransby’s victorious libel suit, the generations, so the Monros—the experience, or competence, the jury’s derisory award of £100 unimaginatively named Alexanders system was similarly unpopular damages made plain that relative I, II, and III—maintained a steely with patients—should they live to values were no longer sufficient grip on Edinburgh University’s voice a complaint. When William recommendation for a medical job. chair of anatomy for 126 years. Lucas succeeded his father at Guy’s Uncle Astley’s pleading that young Admittedly there were in 1799, his butchery became so Bransby would make a “brilliant disadvantages. Impatient sons and notorious that one trainee was put operator”—given time—would nephews had to bide their time off surgery for good: the young probably cut little ice even today. until dad or uncle retired through John Keats sought employment Wendy Moore is a freelance writer and author, ill health or died—although given elsewhere. After witnessing Lucas London [email protected]

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Medical classics The casualties of Waugh Extensile exposure By Arnold K Henry My father was not memoranda to the First published as Exposure of the Long very good at telling BETWEEN great ones of the Bones in 1927 THE LINES jokes. If something earth on such sub- Arnold K Henry was a remarkable man. Born in 1886, was a fact he couldn’t Theodore Dalrymple jects as the fate of he graduated from Trinity College Dublin in 1911 and leave it out, and over- major rivers, and his became fellow of the Royal College of Surgeons of Ireland inclusiveness is not daughter, Angela, in 1914. In the first world war he served as a surgeon an aid to mirth. Still, is so impressed on in both the Serbian and the French armies and was he had a repertoire a visit to her father decorated by both. He was accompanied by his wife, Dr of old favourites, and by the efficiency of Dorothy Milne Henry, who was his close collaborator and one of them, which Mr Loveday, who assistant. He went on to work as a surgeon in Dublin, then as professor of surgery at the University of Cairo and he told many times, tells her that many at the Postgraduate Medical School at Hammersmith, concerned what in years ago he made and in 1947 returned to Dublin as professor of anatomy. those days was still the slight mistake In 1927 Henry published a book entitled Exposure popularly known as of knocking a girl of the Long Bones, which was revised first in 1945 to the loony bin. off her bicycle and Extensile Exposure Applied to Limb Surgery and then An inmate showed then strangling her, in 1957 as a second edition entitled simply Extensile the chairman of the that she vows to Exposure. This volume remains an invaluable reference for surgeons of all persuasions, but particularly those board of visitors secure his release. who operate on the limbs. around the establish- Mr Loveday tells The book covers a lot of ground; from exposures in the ment, and did so with What exactly is her that he has only neck, the upper extremity, the thorax, the pelvis, and the such lucidity that the Waugh satirising in one small ambition, lower extremity. As the title suggests, the approaches chairman asked him his story? Not least, but does not want to are extensile. For example, the nerves of the brachial why he was an inmate surely, the do-gooding say what it is. plexus can be followed from the neck into the shoulder and the arm. Where other anatomical texts appear dry at all. He replied that propensities of the This she does, and he didn’t know, and a meeting is held in and uninteresting, Henry’s descriptions of the practical well-placed aspects of surgical asked the chairman the asylum to send Henry’s description exposure are fascinating to help him secure his Mr Loveday off to of how his technique and are interspersed release. The chairman his freedom. The for pulmonary with anecdotes from his promised to do so. doctor assures him extensive surgical career. Just as he was leaving the asylum, the that he is so highly esteemed by both embolectomy He suggests those not chairman felt a blow with a brick on the staff and patients that there will always evolved when following his advice “will back of his head. be a place for him if he does not like operating on three only make a mess.” The “Don’t forget now,” said the inmate, life outside. patients is published “striped (and sometimes flashy)” sandwich of waving to him. Mr Loveday is back within two despite the fact that supinator containing the This joke is, in essence, identical to hours; and all too predictably, he has none survived posterior interosseous the plot of Evelyn Waugh’s short story knocked a young woman off her bicy- nerve is “thin, so do Mr Loveday’s Little Outing. cle and strangled her. He announces not nick the nerve.” The vessels on the deep surface of Lord Moping is committed to the with the greatest pleasure that now he gluteus maximus sprawl like those of the placenta. Henry County Asylum for Mental Defectives will never be released from the asylum is refreshing in his honesty. His description of how his (a term still widely in use during my again. He had never really wanted to go technique for pulmonary embolectomy evolved when childhood, although educationally sub- in the first place. operating on three patients is published despite the fact that none survived. normal was taking over) when he tries What exactly is Waugh satirising Henry clearly has a sense of humour. He can’t resist to hang himself during his wife’s annual in his story? Not least, surely, the do- a dig at other texts, describing the “huge great sciatic garden party. gooding propensities of the well-placed, nerve” as the one “oasis of description” Gogarty could Lady Moping refuses to counte- who are inclined to take up causes find in Cunningham’s anatomy. The whole is written in a nance a more expensive establishment whimsically as a means to mere self style reflecting a classical education; in Henry’s view the because she has been so humiliated gratification, without much thought for hamstring tendons and vastus lateralis are the “Scylla by his social faux pas; but the richer the possible consequences. and Charybdis” between which the gluteus maximus may be palpated. His description of the function of lunatics have a wing of their own in Of course, these days Mr Loveday gluteus maximus is a particular delight. the asylum, where they are allowed to wouldn’t have been released without a There is no doubt that Henry was a man of powerful dress as they please and to have a din- proper risk assessment and follow up intellect, with an enquiring and analytical mind. This ner party every year on the anniversary arrangements. book contains the distilled experience of many years of their committal. I’m not sure that would have pre- of practice. It is an apt legacy. Fifty years have not Mr Loveday, another long term served the young woman on the bicy- diminished its relevance and usefulness. inmate, acts as Lord Moping’s amanu- cle, however. Craig Gerrand, consultant orthopaedic surgeon, Freeman ensis during his residence in the asylum. Theodore Dalrymple is a writer and retired Hospital, Newcastle Upon Tyne [email protected] Lord Moping is forever dictating doctor

BMJ | 16 june 2007 | Volume 334 1277 OBITUARIES For the full versions of articles in this section see bmj.com

Miles Weatherall and Josephine Alice Coreen Weatherall (née Ogston) Leading pharmacologist in academia and industry, and collator of fetal anomalies

Miles Weatherall occupied work on identifying and prevent- prominent positions in both ing fetal anomalies. academic life and the research Jo conducted health serv- side of the pharmaceutical ice research studies at Charing industry. He did a BSc in phar- Cross Hospital during 1960-2. macology by thesis in 1941, In November 1963 she reviewed a year before he studied the trends in morbidity and mortal- subject in the medical course, ity attributed to thromboembolic and immediately after qualify- disease as a fellow at the London ing was asked to prepare a top School of Hygiene and Tropi- secret report on mepacrine, cal Medicine. From 1965 she which had been invented was a medical statistician at the in Germany before the war General Register Office (now and was thought to be useful the Office for National Statistics) against malaria. Miles could not working on improvements in re- believe that the War Office hadn’t became professor of pharmacology in the porting and analysing deaths in confidential thought of this before, musing that the University of London in 1958. inquiries into maternal deaths and in multi- job had perhaps been done five times over, In 1967 he moved to the Wellcome ple cause coding of deaths. each time so secretly that no one had ever Research Laboratories at Beckenham, Kent, Jo helped to establish a system for routine heard the outcome. Thirty years later he as head of the therapeutic research division, national reporting of congenital anomalies came back to mepacrine at the Wellcome, becoming director of establishment in 1974. by birth attendants in England and Wales. finding his 1943 report quite handy. Retirement in 1979 brought a number of In the mid-1960s she was a founder member After house jobs Miles was classified as new educational activities, including work of the International Clearinghouse for Birth unfit for military service owing to a sus- at Chelsea College and preparing an index Defect Monitoring Systems. This work cul- pected peptic ulcer, which was to incon- for Medical History. Miles wrote several nov- minated in her role from 1978 to 1984 as venience him for much of his profes- els and A Weatherall Memoir, all published the founding project leader of the European sional life. With a grant from the Medical privately. His interests included railways, Register of Congenital Anomalies and Research Council he started pharmacolog- gardening, and wine, and he was proud to Twins (EUROCAT), then based in Leuven, ical research in Edinburgh under Professor serve on the committee of the Wine Society. Belgium, and now in Belfast. J H Gaddum. This became a lectureship, In his last years he was largely housebound Throughout her career Jo was a loving and in 1949 Miles was encouraged to apply devotedly looking after his wife, Jo, during teacher and friend to her children and grand- for a similar post at The London Hospital her illnesses; after 62 years of marriage, she children. She and Miles shared their interest to start a new department. predeceased him by a few months (see next in good food and wine with family and He established a thriving forward look- obituary). He leaves three daughters and friends, offering an open house. Their large ing department. Academic posts, as seven grandchildren. garden was an escape from work pressure opposed to purely research appointments, Estlin Waters and a continuing joy in retirement until ill enabled him to become more broadly Miles Weatherall, professor of pharmacology, health and disability took hold. They raised involved in general scientific education. London University, and director of establishment, funds for the Arthritis Research Campaign His department developed stimulating Wellcome Research Laboratories (b 1920; q by opening it to the public on more than one seminars that were attended by many out- Oxford 1943; BSc, MA, DM, DSc, FI Biol), died from occasion. side the boundaries of pharmacology. ischaemic heart disease on 8 March 2007. Miranda Mugford, Alison Macfarlane Miles wrote Statistics for Medical and With help from Alison Robinson, Rosamund Other Biological Students jointly with Married to Miles Weatherall (see previous Weatherall, Bev Botting, Michel Lechat, Brian L Bernstein in 1952, a book at least a obituary), pharmacologist, in 1944, Jo first Furner, and many others quarter of a century before its time so far worked in physiology, including publishing Jo Weatherall, founding project leader of the as medical education was concerned. He jointly with him on the effect of dithiols on European Register of Congenital Anomalies and also wrote the popular (in both senses) time to death in poisoned rats. Her work on Twins (EUROCAT) (b 1922; q Edinburgh 1945; BSc, Scientific Method and In Search of a Cure: fetal physiology in Oxford during 1957-9 laid FFCM), died from respiratory failure on 17 October a History of Pharmaceutical Discovery. He the foundation for her later epidemiological 2006.

1278 BMJ | 16 june 2007 | Volume 334 obituaries

William (“Bill”) Bingham served then consultant senior lecturer at St Khalid Tariq Al Naib on rescue ships in the North Robert John Jameson Thomas’ Hospital, where he wrote Atlantic and subsequently became his MD thesis on the haemolytic principal medical officer for the effect of dapsone. In 1973 he Mediterranean Fleet. Appointed as was a singlehanded consultant consultant anaesthetist to Lurgan haematologist at the Bristol Royal and Portadown Hospital and later Infirmary and Weston super Mare, in Belfast, he initiated respiratory a post he held until retirement in intensive care in Ulster, being the 2001. A member of the advisory first person in Ireland to paralyse appointments committee for and ventilate patients with tetanus consultant haematologists in (1950). His seminal paper on the south west region, Geoffrey Assistant professor of medical balanced anaesthesia for caesarean Former general practitioner Bath (b also helped to develop the Avon microbiology and vice dean for section established the standard of 1917; q London 1943), d 18 April Haematology Unit, now a regional scientific affairs Al Nahrain Medical care. He amalgamated the Armagh 2007. service with six haematologists. School, Baghdad (b 1963; BSc Kuwait and Down divisions of the BMA as In 1951 Robert Jameson was Professionally, he was interested in 1987; MSc, PhD), murdered in Iraq on chairman, and he was chairman of appointed to a singlehanded the haematological manifestations 30 March 2007. staff of both the Royal Maternity and practice in Bath after working in of systemic disease. His leisure Khalid Tariq Al Naib was kidnapped Ulster Hospitals. Predeceased by hospital as an obstetric registrar. interests included horse riding, and murdered in Iraq on the day a son, he leaves a wife, Nora; three Obstetrics remained important gardening, theatre, and ornithology. he returned from sabbatical at children; and five grandchildren. to him throughout his career. His He leaves a wife, Jane, and a son. the Peter MacCallum Cancer J S Bingham, E A Barnett practice was the first in Bath to Helena Daly, John Hudson Centre in Melbourne, Australia; have a health visitor and practice death threats had been sent to nurse. In his practice he observed his office in Baghdad while he Stuart Gordon Adam Forsyth a large family with “nail patellar” Anthony Robert (“Bob”) was away. In addition to teaching syndrome, and in 1956 published Teuten immunology to undergraduates a paper with two coauthors in the and conducting his own research in Annals of Human Genetics on the Former general practitioner Brent (b medical microbiology, Khalid also linkage of this syndrome to ABO 1925; q St Mary’s Hospital, London, worked with non-governmental blood grouping. A founder member 1949), died from heart failure on organisations, reporting the of the Royal College of General 6 January 2007. health status in Iraq, establishing Practitioners, he contributed greatly After qualifying, Bob Teuten joined a blood bank in Duhouk as part to patient care and the medical the Royal Army Medical Corps, of a humanitarian programme, community. His gracious manner serving partly in Saudi Arabia. He and improving Iraqi laboratory endeared him to patients—some still subsequently joined the Territorial services for tuberculosis. One of his Former general practitioner Tonbridge, asked about him 22 years after his Army, becoming a major. He joined objectives on sabbatical was to learn Kent (b 1922; q Cambridge/University retirement. He had a deep Christian his father’s practice in Harlesden in how to improve scientific training College Hospital, London, 1945; DCH), faith and was active in church life. 1952 and took on full responsibility and development in Iraq. He leaves d 12 March 2007. Paul Booth, Angela Jameson, David in 1954. He was one of the first a wife, Manal al Musawi, and a baby In 1949 Stuart became the fourth Jameson doctors to move to the Craven Park son, whom he saw once. partner in the largest practice in Health Centre in Stonebridge Park Saad Shakir Tonbridge. He gained the diploma on its establishment in 1971, where of child health in mid-career and Geoffrey Laurence Scott he remained until his retirement in for many years stood in for the 1995. His many interests included William Bingham consultant paediatrician at Pembury cricket, ornithology, Australian Hospital in his absence. He also stamps, gardening, and English helped in the training of Red Cross romantic poetry. He leaves a wife, and St John Ambulance volunteers. Margaret, and three children. Stuart played the flute in the Richard Teuten Tonbridge Philharmonic Orchestra, of which he was later president, and Advice served as chairman of the Tonbridge We will be pleased to receive Musical Society. After his retirement obituary notices of around 250 in 1987 he gained the diploma in Former consultant haematologist words. In most cases we will be able philosophy of the University of Kent Bristol and Weston super Mare (b to publish only about 100 words in Former consultant anaesthetist Royal and actively supported the Tonbridge 1936, q Cambridge/St Bartholomew’s the printed journal, but we can run a fuller version on our website. We will Victoria and Maternity Hospitals, Ulster Old People’s Society, later Age Hospital 1961; MA, MD, FRCP), take responsibility for shortening. Hospital, Belfast (b 1916; q Queen’s Concern, the hall in which they meet d 3 February 2007. We do not send proofs. Please give University, Belfast, 1941; MD, FFARCSI, being named after him. He leaves a After qualifying first in his year a contact telephone number and, FRCA), died from bronchopneumonia wife, Jean, and five children. and working at Barts, Geoffrey where possible, supply the obituary on 21 March 2007. John Ford Laurence Scott was lecturer and by email to [email protected]

BMJ | 16 june 2007 | Volume 334 1279 minerva

An Australian doctor has received an email offer from South Africa which suggests he is being considered for an award as a “distinguished contributor to medical knowledge.” Part of the award is said to involve naming a wing in a new oncology centre after him. As much as he’d like to think he was worthy of such recognition, the doctor in question describes himself as a “minor player in radiation oncology” and warns others that this is likely to be another version of the notorious Nigerian money laundering scam and should be ignored.

Patients with newly diagnosed type 2 diabetes are at high risk of stroke in the first five years after diagnosis compared with the general An 81 year old woman underwent abdomino-perineal excision of the rectum with the creation of a left public. Researchers in Canada estimate the iliac fossa colostomy for low rectal cancer. Preoperative colonoscopy had also revealed melanosis risk is more than double the rate for the general coli, a condition associated with the use of laxatives causing mucosal pigmentation. Many staff, population, which confirms the need for both medical and nursing, had never seen melanosis coli, particularly in a stoma, and required aggressive management of cardiovascular risk reassurance that this stoma was not necrotic but was healthy. This was confirmed by its function and warmth on palpation and the patient’s general state of wellbeing. in these patients right from the start (Stroke 2007;38:1739). Alexander Harris, preregistration house officer ([email protected]), Gordon Buchanan, consultant colorectal and general surgeon, Charing Cross Hospital, London W6 8RF

Children born with insufficient numbers of neutrophils are prone to sepsis, but they can level of the student’s training. But the frequency choice, aptitude, or relevant training, and be treated successfully with G-CSF (granulocyte of interruptions (per minute) did not vary hospital juniors remain unsupervised for much colony stimulating factor) to reverse the according to the level of the learner. In 40% of of their clinical work. In contrast, GP registrars neutropenia. What’s interesting is that, although trainees’ presentations, the teacher interrupted are in effect supernumerary in their practices G-CSF can improve the cell count, it does not in order to give an assessment and sometimes a and have access to constant supervision (QJM correct the underlying functional deficiency plan before the trainee had done so. Only 8.3% 2007;100:393-4). of the neutrophils in defending against micro- of learners said they found the interruptions organisms. Scientists report that the expression disruptive (Academic Emergency Medicine The quality of drinking water in many developing of the polypeptides responsible for the 2007;14:521-5). countries remains poor. A community based antimicrobial machinery of these cells is almost longitudinal study conducted over two years absent in those children who carry the mutant There may be personality traits that can help in India found that 47.7% of hand pumps and gene even when they are subsequently treated doctors distinguish between people who are 15.9% of taps were supplying contaminated with G-CSF (Blood 2007;109:4716-23). developing dementia with Lewy bodies and water (Bahrain Medical Bulletin 2007;27:53-6). those with Alzheimer’s disease (Neurology The situation was worse in the pre-monsoon and Toilet trained children who need to provide 2007;68:1895-901). The most important traits monsoon seasons. Education about methods of midstream urine samples should be cleaned are diminished emotional responsiveness, household disinfection is critical. around the perineum with soap beforehand relinquishing hobbies, growing apathy, and to reduce contamination rates (resulting in hyperactivity with no purpose. Identifying A study of more than 12 000 grandparents in unnecessary treatment with antibiotics), these, together with the presence of visual the United States concludes that looking after according to a study in Pediatrics (2007;119: hallucinations, should improve the identification grandchildren is perfectly safe and may even e1288-93). Children randomised to the cleaning of people with dementia with Lewy bodies. benefit the grandparents’ health (Washington group were less likely to have a positive urine Times, 1 June, www.washingtontimes. analysis result than those in the non-cleaning A GP educationalist recently re-entered the com). Whether it’s a full time occupation or group (21% v 37%). world of hospital medicine. He was shocked just occasional duty, grandparents suffer no to discover that, while GP education has been ills. Grandmothers, in fact, reported “modest When medical students present cases dramatically transformed over the past quarter of improvements” in their health, tended to exercise they’re often interrupted by their teachers. An a century, the development of medical training in more, and had less depression. These findings observational study carried out in one teaching hospitals seems to have stood still. Consultants, fly in the face of a media barrage that, over the centre found that the number of interruptions he says, find themselves in training roles by years, has focused on the alleged problems for and duration of presentations decreased with the force of circumstance rather than through grandparents who take care of their grandchildren.

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