Editorials

Australia should lead in the effort to reduce the huge burden of non-communicable diseases When it comes to global health, the international aid effort is almost entirely focused on the immense burden that communicable diseases inflict on the world’s low- and middle-income nations. But the world is also facing what United Nations (UN) Secretary-General Ban Ki-moon describes as “a public health emergency in slow motion”.1 Across the globe, non-communicable diseases (NCDs) — principally heart disease, cancer, diabetes, kidney disease and chronic lung disorders — are imposing ever greater burdens on individuals, families, health systems and economies. The World Health Organization believes that NCDs now account for some eight million premature deaths (before the age of 60 years) each year in low- and middle-income countries. Altogether, there are an estimated 35 million NCD deaths each year, with around 80% occurring in low- and middle-income countries.2 Deaths from NCDs are projected to increase by 17% worldwide in the coming decade, with the largest increase (27%) occurring in Africa. The highest absolute number of deaths will be in Australia’s local regions: the Western Pacific and South-East Asia.2 And yet, much of this burden is avoidable, with around 80% of heart disease, stroke and type 2 diabetes and over a third of cancers deemed preventable by eliminating shared risk factors, including tobacco use, poor nutrition, physical inactivity and alcohol misuse. Despite the growing burden that NCDs inflict on the developing world, a pittance — just 2.3% — of overall development assistance for health was dedicated to NCDs in 2007.3 This is even more surprising given the impact that NCDs have on productivity. The World Economic Forum, an organisation of private, mostly multinational companies, already considers chronic disease in both developed and developing nations to be a major risk to the global economy.4 While prevention and treatment of NCDs make sound economic sense, calls for help from developing nations have met with little response. The UN said in a report on NCDs last year that “requests for technical support to scale up efforts, through aid and expertise, remain largely unanswered”.5 There is, however, some light at the end of the tunnel. Things are starting to change. After a concerted campaign by international chronic disease organisations and collective action by Commonwealth and Caribbean countries, the UN has agreed to hold a special summit on NCDs, the first health summit since the landmark HIV/AIDS gathering a decade ago. To be held in New York on 19–20 September 2011, the summit will consider what action might be taken to help all countries, but especially those of low and middle incomes, to meet the NCD challenge. It is clear that NCDs must become a key part of the global health and development agenda. This is the goal of the NCD Alliance,6 a coalition convened by the World Heart Federation, Union for International Cancer Control, International Diabetes Federation and the International Union Against Tuberculosis and Lung Disease. While the global campaign is being waged, an Australian group — Australians for Global Action on NCDs — has formed to encourage the Australian Government to help lead global change, by seeking tangible outcomes from the UN summit and playing a strong role beyond it, particularly in the Western Pacific region. Although much remains to be done at home, particularly for Aboriginal and Torres Strait Islander peoples and those from lower socioeconomic backgrounds, Australia should also boost efforts to assist developing nations in our region escalate their NCD-prevention efforts and improve screening, early detection, treatment and palliation. A gathering organised by our group at Parliament House on 2 March 2011 will help sell the message to federal politicians, many of whom are already sympathetic to the cause. Over the coming 7 months, the world will be looking to countries with strong records in prevention and management of chronic disease to help set the agenda for the UN summit on NCDs. While this includes nations across the income spectrum, Australia should be thrusting its hand in the air. We have much to offer. For example, Australia has been a leader in tobacco control. Robust action, including price hikes, comprehensive advertising bans and investment in social marketing, has seen smoking rates plummet in Australia, from 34% of the adult population in 1980 to less than 20% today.7 So, what do we want from the UN summit? Work is underway to define the best possible outcomes, but there is growing international consensus among NCD Alliance members around six primary objectives: Governments must have NCD plans and be accountable for progress. The existing WHO Framework Convention on Tobacco Control should be fully implemented. There must be a global commitment to prevention of NCDs. Globally agreed approaches to treatment and care must be forged. Resources must be available to deliver effective interventions and enhance the capacity of developing nations to meet the NCD challenge. NCDs must be prominently included in the targets that will follow the current Millennium Development Goals. Reducing the burden of NCDs will take dollars. It will take courage. And it will take long-term commitment. But it will pay for itself many times over by helping countless millions of people to lead longer, healthier, happier and more productive lives.

Australians for Global Action on NCDs*

Palliative care is becoming fundamental in the starting line-up of care choices For Australian patients with advanced, incurable illness, particularly cancer, the option of referral to specialist palliative care services can seem to be a random and discretionary default option that is sometimes called on when all possibilities for life-extending treatment have been exhausted or cannot easily be accessed. Palliative care services (distinct from palliative chemotherapy) provide a broad range of inputs to patients and their carers and loved ones, including specialised medical and nursing management and advice on symptom control; psychological, emotional and spiritual support; practical nursing care; advice and assistance with goal setting and end-of-life care; and bereavement counselling and support. Despite offering these and other unique strategies in the field of cancer management, these specialist palliative care services sometimes stay on the substitute’s bench until called on late, when all else has failed. In Australia, despite having had principles of goal setting and broad palliative care education as part of the medical curriculum for over 20 years,1-3 and despite evidence of the benefits of referral to specialist palliative care services,4 only 42% of patients who die of advanced cancer and other terminal illnesses in the country’s busiest acute hospital are referred to a specialist palliative care service.5 Patients with haematological malignancies are referred less frequently than patients with solid tumours.6 Although oncologists in Australia report that they favour early referral for specialist palliative care, with a concurrent rather than sequential model of care,7 patients are usually referred late. In one large, integrated Australian palliative care service, patients had a median length of survival after referral of 54 days, representing the final 17% of their illness duration.8 Perceived barriers to improving palliative care referral and provision include inadequate communication about goal setting and resuscitation orders; inadequate symptom control; and lack of resources, including inadequate bereavement counselling of caregivers.7 A Queensland senator recently called Australian palliative care services “an under-resourced shambles”.9 In Australia and elsewhere, there have been increasing efforts to more accurately define the benefits or otherwise of early referral to palliative care services for patients with an incurable and progressive illness. However, research has been difficult, and randomised controlled trials have not been of high impact. Now, the results of two recent prospective, randomised studies from the United States10,11 will help to broaden Australian clinicians’ and the public’s understanding of the role of specialist palliative care services in the care of patients with advanced, incurable cancer and the advantages of early referral. Although the evidence from these studies has limited application in Australia because of differences in the US and Australian health care systems, the models of care being tested are similar to current Australian models, and the results have the potential to significantly shape practice and policy in this increasingly important part of health care.9 A non-blinded randomised controlled trial reported by Temel and colleagues10 provides a watershed moment in oncology and palliative care. One hundred and fifty-one ambulatory patients referred to an outpatient thoracic oncology clinic for newly diagnosed non-small cell metastatic lung cancer were randomly allocated to standard oncology care with or without referral to a palliative care team. The primary outcome was change in health-related quality of life at 12 weeks. Patients in the early palliative care group had better quality of life and fewer depressive symptoms compared with those receiving only standard care (Box). The various goals of new interventions in cancer treatment include improving survival; reducing treatment toxicity; improving quality-of-life scores (eg, mood); and reducing the financial costs of treatment. This study achieved all these goals with just the modest intervention of an average of four visits from the specialist palliative care team in the first 12 weeks. Importantly, the median survival time of 8.9 months was at least as good as would be predicted and expected for the control group. The improvement in overall survival of 2.7 months (30%) for the intervention group who were referred for early palliative care was equal to or greater than that achieved for comparable patient groups with chemotherapy versus best supportive care12 or the addition of the new and very expensive targeted agents cetuximab or bevacizumab to chemotherapy.13,14 It was achieved despite significantly fewer patients receiving aggressive end-of-life care. The size of the survival benefit may have been reduced because 14% of the control group also received early referral to a specialist palliative care service for symptom control and had 1–2 palliative care visits during the 12 weeks. A survival advantage from early palliative care referral has been suggested previously,15 but will need to be replicated by studies in other care settings and in patients with other types of cancer. Possible weaknesses of this study are the lack of blinding and lack of patient comorbidity data. Extra time spent with health care professionals, rather than any specific palliative care intervention, may have contributed to the improvements seen. But if this were so, this effect would also have been expected in studies showing benefits of chemotherapy plus best supportive care versus best supportive care alone, whereas no difference was shown in survival advantage between these groups.12 Also, even though the patient groups were balanced for types of chemotherapy and other treatments at enrolment and for the number of courses of chemotherapy during the study, more detailed data on specific chemotherapy regimens are lacking. Wright and colleagues11 followed 333 patients with advanced cancer from their enrolment until their death. Those referred to specialist palliative care services had better outcomes when treated outside an acute hospital (Box). Assessment of their carers at enrolment and after the death of the patient showed that those who were assisted in providing care at home until the patient’s death had significantly less risk of developing post-traumatic stress disorder or prolonged grief disorder. In the future, as we seek to confirm and understand more about how these improvements were achieved in patients receiving specialist palliative care, early referral for palliative care should become part of all arms of any randomised trial of advanced cancer treatment, particularly when a new treatment is being compared with best supportive care or current best treatment. The results of the two studies discussed here provide the best evidence yet for the multiple benefits of early referral to palliative care services in the care of patients with advanced, incurable cancer. They show that early referral can improve all measurable outcomes for patients by as much as, or more than, new and expensive treatments. Further, they show that early referral can help patients and carers better understand and choose between their treatment options near the end of life, reducing futile use of finite medical resources, debilitating treatments such as continuing cycles of chemotherapy in very advanced stages of illness, and acute in-hospital interventions at the end of life. The incidence of subsequent emotionally and financially debilitating psychological and psychiatric sequelae in the carers of these patients can be reduced. Because of new high-quality evidence, palliative care is rapidly moving from being an ancillary and sometimes discretionary medical treatment option to being fundamental in the starting line-up of care choices for patients with advanced cancer. If early referral for specialist palliative care were an expensive new drug, it would quite appropriately be marketed as a major advance in improving the care of patients with incurable cancer. Two recent US studies showing benefits of early specialist palliative care in patients with advanced cancer: overview Temel et al10 Research question: Does early referral of ambulatory patients with newly diagnosed metastatic non-small cell lung cancer to a specialist palliative care service affect patient-reported outcomes, use of health services and quality of end-of-life care? Design Non-blinded randomised controlled trial; 151 lung cancer patients referred to an outpatient clinic Standard oncology care versus standard care with referral to a palliative care team (seen within 3 weeks, and at least monthly until death) Groups well balanced for all known prognostic factors, initial cancer therapy, and baseline quality of life and mood Quality of life and mood assessed at baseline and 12 weeks Data on end-of-life care derived from medical records Findings Patients assigned to early palliative care received an average of four palliative care visits in 12 weeks (range, 0–8 visits) Patients in the intervention group had better quality of life than patients assigned to standard care Proportion of patients with clinical depression decreased in the intervention group from 22% to 16% and increased in the control group from 25% to 38% (P = 0.01) Fewer patients with early palliative care compared with standard care received aggressive end-of-life care (33% v 54% of those who had died by time of analysis; P = 0.05). Median survival was significantly longer among patients receiving early palliative care (11.6 v 8.9 months; P = 0.02) Wright et al11 Research question: Is the place of death for patients with cancer associated with patients’ quality of life at the end of life and psychiatric disorders in bereaved caregivers? Design Prospective, longitudinal multisite study; 333 patients with advanced cancer and their caregivers Patients followed from enrolment to death (median, 4.5 months) Quality of life at end of life assessed by caregiver report within 2 weeks of death Caregivers’ mental health assessed at baseline, and 6 months after patient’s death Findings Patients who died in an intensive care unit or hospital experienced more physical and emotional distress and worse quality of life at the end of life compared with patients who died at home with palliative care Death in an intensive care unit was associated with a greater risk of post-traumatic stress disorder in carers compared with death at home with palliative care (21.1% v 4.4%; P = 0.02) Death in hospital was associated with heightened risk for prolonged grief disorder in carers compared with death at home with palliative care (21.6% v 5.2%; P = 0.02)

Ian E Haines MB BS, FRACP, FAChPM

To respond to changing population and workforce needs and expectations, evidence must inform policy investment, implementation and evaluation We all understand evidence-based practice, but what about evidence-based reform? The Australian Government emphasises the need to strengthen the primary health care (PHC) system1 and has undertaken to boost Australia’s health workforce by funding Health Workforce Australia (HWA)2 and committing policy investments in three areas in its National Health and Hospitals Network report:3 Providing additional general practitioner, medical specialist and PHC training places. Improving PHC service delivery through GP Super Clinics. Improving planning and coordination of PHC services through Primary Health Care Organisations (PHCOs, also known as Medicare Locals). Does the government have an evidence base for its primary health care workforce reforms? The need for evidence-informed policy making and implementation has been emphasised4 — rightly so, as the government needs to be transparent and accountable for its decisions and actions. Because policy implementation is complex and context-dependent, reflection is required on the evidence that informs policy implementation, and the likely success of such reforms. We acknowledge that multiple “policy vectors” (eg, practitioner and patient realities) also need to be considered. Although we focus on the Australian context here, similar issues and debates exist internationally.5,6 This editorial does not summarise evidence underpinning the PHC workforce,7,8 but draws on it to consider important strategic, evaluative and contextual research questions relating to the government’s three policy investment areas. Providing additional GP, medical specialist and PHC training places. To ensure that the additional investments are targeted, research questions should include: Strategic questions. Where could training capacity be increased? What additional resources are required to maximise the effectiveness of these training places? How do additional training places address existing areas of workforce shortages? Evaluative questions. Do medical schools and training programs improve consumer access to services and meet the needs of communities over time? Contextual questions. Are these the most appropriate health professional groups to expand? Are there different models of care that might be more relevant to contemporary practice or, more importantly, practice in 2020? Data from the Medicine in Australia: Balancing Employment and Life (MABEL) longitudinal survey, the Medical Schools Outcomes Database, Medicare, HWA surveys, and national registration may help to address these questions. For example, as part of the first wave of MABEL, a discrete-choice experiment was completed by 532 junior doctors in 2008 before they chose a specialty training program.9 In a policy simulation, researchers found that increasing GPs’ annual earnings by $50 000 and increasing opportunities for procedural or academic work could increase the number of junior doctors choosing general practice by between 8 and 16 percentage points (representing 212–376 junior doctors per year). These results can help policymakers to address the unbalanced supply of doctors across specialties. Improving PHC service delivery through GP Super Clinics. Twenty-three new GP Super Clinics will be funded and 425 existing PHC facilities will be upgraded to improve team-based care. To efficiently plan the locations and roles of the new GP Super Clinics, research questions should include: Strategic questions. Are GP Super Clinics located in areas of workforce shortage and hence eligible for additional support? Do GP Super Clinic workforce skill mixes and skill sets match population health needs? Evaluative questions. What impacts are GP Super Clinics having over time on patient care and on workforce models of care and skill sets? Contextual questions. Given the importance of team-based care, what role can interprofessional learning have in GP Super Clinics? Improving planning and coordination of PHC services through PHCOs. PHCOs will be established to improve the planning and coordination of PHC services at the local level.10 To efficiently plan the locations and roles of PHCOs, research questions should include: Strategic questions. How does the profile of the local PHC workforce need to be expanded, retrained or shifted in relation to population health profiles? Evaluative questions. Can PHCOs measure and predict access problems (eg, for refugees and Indigenous people) and hence inform the extent to which PHC services need to be tailored to these groups? Contextual questions. How can different models of care that focus on patients’ needs, and learning programs that inform patient choice, be developed to improve health literacy and reduce the demand on health services? The above policies should also be considered from an equity perspective: What are the equity implications of each reform (especially GP Super Clinics and PHCOs) from a workforce point of view? Will these policies exacerbate imbalance in the workforce, which is already unequally distributed on the basis of socioeconomic need? HWA and the National Primary Health Care Strategy provide the opportunity for these questions to be addressed. However, a national PHC workforce policy is needed to guide key policy reform investment, development, implementation and evaluation. To respond to changing population and workforce needs and expectations, evidence must inform policy investment, implementation and evaluation. Until we have a better understanding of how evidence is being used, there will be limited knowledge about what makes policy implementation work, for whom and in what circumstances.

Lucio Naccarella BSc(Hons), GradDipMHS, PhD · Peter M Brooks AM, MD, FRACP · Bill Newton BA · Danielle Butler MD

Joining university to clinical service, research to practice The model of the academic health science centre (AHSC) arose decades ago in the United States,1 and is now internationally well established, with 17 centres in Canada, eight in Holland, five in the United Kingdom, two in Singapore, but none in Australia. An AHSC is where a leading university joins with a major tertiary health care provider in a tripartite mission of excellence in clinical service, research and education. AHSCs drive a care continuum from innovation, to bedside, to the community, endeavouring to ensure that the latest advances and highest standards reach patients. They are so well established abroad that the debate has moved on to extending AHSCs into systems or networks to embrace primary health care and global responsibilities.2 Curiously, Australia’s National Health and Medical Research Council (NHMRC) makes no mention of AHSCs in its 2010–2012 strategic plan,3 despite its own external review (the Zerhouni Review) advocating creation of at least a few Australian centres of world-class excellence in translational and clinical research.4 Similarly, AHSCs did not attract serious discussion in the report of the Council of Australian Governments (COAG) National Health and Hospitals Network (NHHN) Agreement (April 2010), although the detail at least acknowledges that engagement with university clinical schools and research centres is critical to translating clinical research into practice, ongoing professional development and training the next generation of clinical leaders.5 Strong advocacy for AHSCs to be introduced in Australia has apparently been ignored,6,7 with Brooks warning that our nation is failing to capitalise on global developments in academic medicine.7 So what are the barriers? First, there is a culture clash between federally funded autonomous universities and state-funded hospitals managed as a separate conglomerate in each state and subject to local politics and regional priorities. Indeed, the emphasis in state health departments, it seems, is more on homogeneity than the excellence strived for in academia. This engenders turf wars between universities and hospitals over their diverse missions, priorities, operational frameworks and employment conditions, with process and contracts frustrating attempts to bridge the gap. Cost shifting replaces what should be cost sharing. The second barrier is that the three AHSC pillars — research, education and health care — are overseen by three separate federal government departments and thus three separate ministers. Third, there are additional players in the research sector — the independent medical research institutes — who, although affiliated with universities and tertiary hospitals, have at times eschewed translational links with clinical medicine in favour of basic science. Finally, Australian health care is delivered in a pluralistic mix of private and public funding. Yet none of these issues is unique to Australia or insurmountable, especially when one considers the complexities of the US health care environment where AHSCs began. Cultural cringe may be a further hurdle for AHSC advocates. The NHMRC has foreshadowed the concept of “advanced health care centres”,8 seemingly in response to sensitivities among its political masters about use of the term “academic”. Surely, however, the Australian public are now mature enough to embrace excellence rather than mediocrity in health care, just as they do in sport? In fact, perceived anti-intellectualism is not uniquely Australian, as the case for retaining the term “academic” similarly needed pressing in the UK. Simply put, the best doctors treat patients, do research and train tomorrow’s health care providers. There is now an international association of academic health centres,9 whereas a web search for the “advanced” variant suggests instead a primary and community care focus. The advent, in mid 2011, of Local Hospital Networks, a central plank of the COAG NHHN Agreement,5 offers a pivotal opportunity to introduce AHSCs. Indeed, the simultaneous introduction of Medicare Locals, organisations intended to integrate and coordinate primary care services, provides a serendipitous platform to extend AHSCs into primary care. Ring-fencing hospital leadership from state health bureaucracies will be essential, particularly given the watered-down version that survived COAG. We should not underestimate the challenges of change management, which will require both top-down and bottom-up approaches to unite hospitals and universities, primary care and medical research institutes in a single mission. The choice of governance method is perhaps best determined locally;10,11 an integrated model with a single organisational structure is the ideal, but affiliated models may be more achievable with multiple partners. The NHHN should foster economic support for AHSCs through the 60% federal funding proposed for research and training in public hospitals (100% in primary care),5 and it will be crucial that new monies be spent at the interface of training, service and research. The real challenge will be winning the hearts and minds of federal and state politicians. As in Europe and North America, politicians will need convincing of the economic benefits of linking research to health and embedding research and training as core business in our leading hospitals and primary care networks. Although our international competitiveness in biomedical science is an important pay-off in its own right, the things that swung the argument abroad were improved patient outcomes and cost efficiencies. How many AHSCs does Australia need? With critical mass and existing academic strength as prerequisites, the number will depend on the extent to which AHSCs develop around universities or existing teaching hospitals, or amalgamate to form geographic clusters. Experience in the UK points to competitive national selection being a valid means of testing commitment and the strength of joined-up partnerships. We advocate a similar international review process here, say with four to six AHSCs designated in the first wave. The time is ripe for Australia’s health systems to grasp this opportunity to move from good to great and establish world-class AHSCs in an Australian context.

Nicholas M Fisk PhD, MBA, FRANZCOG · Steven L Wesselingh BM BS, PhD, FRACP · Justin J Beilby MD, MPH, FRACGP · Nicholas J Glasgow MB ChB, MD, FRACGP · Ian B Puddey MB BS, MD, FRACP · Bruce G Robinson MD, MSc, FRACP · James A Angus BSc, PhD, FAA · Peter J Smith MD, FRACP, FRACPA

Effective dementia care depends on early and accurate diagnosis It is predicted that over the next 40 years there will be a fourfold increase in the prevalence of dementia in Australia, as well as considerably more people with milder forms of cognitive impairment.1 To date, despite extensive research, no effective treatment for established dementia is available. As a result, taskforce policymakers conclude that there is insufficient evidence at present to warrant routine screening for dementia syndromes.2,3 However, emerging evidence shows that early non-pharmacological intervention can improve cognitive outcomes for patients with milder forms of cognitive impairment and those at risk of cognitive decline.4 Early diagnosis also enables patients to plan, with their caregivers, for the future, and deal with matters such as enduring power of attorney authorisation, before they lose the capacity to do so. Over two-thirds of people who notice symptoms of cognitive decline consult a physician for evaluation.5 However, up to 90% of mild cases are missed at the initial primary care assessment.6,7 So how can we improve early detection of cognitive impairment, and what evidence base do we have for dementia screening in Australia? A diagnosis of dementia relies on a full mental status assessment, with comprehensive history taking and physical examination. Presently, detailed neuropsychological testing is the gold-standard tool for objectively evaluating the magnitude and pattern of cognitive decline. However, neuropsychological evaluation is costly, time-consuming and not generally available as only specialist psychologists can do it. Consequently, general practitioners and specialist physicians, who evaluate most patients presenting with cognitive complaints, administer brief screening instruments such as the mini-mental state examination (MMSE) to assess cognition. In Australia, the use of such instruments has been propagated by guidelines for prescribing acetylcholinesterase inhibitors. The MMSE has many documented and widely appreciated shortcomings. It lacks diagnostic specificity and is insensitive to patient variables such as extreme levels of education, premorbid ability and poor command of English.8 It has also been criticised for its unsystematic and atheoretical construction, and its poor ability to detect milder forms of cognitive impairment.8,9 The idea that any brief screening tool would have sufficient sensitivity and specificity to diagnose dementia is unrealistic. However, when used as an adjunct to a good clinical history, a more accurate instrument, particularly one that can be serially administered, would potentially increase the reliability of diagnosis. A recent review of screening instruments available for mild cognitive impairment concluded that there are more useful screening tools than the MMSE.10 Some are in use in Australia, including the Addenbrooke’s Cognitive Examination – Revised (ACE-R); the Alzheimer’s Disease Assessment Scale — cognitive subscale (ADAS-cog); and the Montreal Cognitive Assessment battery. In addition, there are other screening instruments specifically validated for use in Australia, such as the General Practitioner assessment of Cognition (GPCog) and Rowland Universal Dementia Assessment Scale (RUDAS). Recently, the ACE-R was validated for use in an Australian population.11 The ACE-R, which incorporates the MMSE, has been shown to have more diagnostic sophistication, with improved sensitivity and specificity values, than the MMSE alone. This is not to say that the ACE-R is without limitations. For instance, it cannot fully assess some aspects of cognitive function (eg, non-verbal skills). Furthermore, the ACE-R takes on average 16 minutes to administer and is therefore unlikely to see much uptake by busy GPs; however, it could be used by nurses working in general practices. As with all screening tools, clinicians using the ACE-R in the primary care setting need to be trained to correctly score and interpret patients’ ACE-R performances. Development of effective dementia treatments depends on earlier and more accurate identification of disease. Cognitive screening tests will continue to evolve, and may in time be replaced with screening for disease-related biomarkers. However, such diagnostic biomarkers have yet to be discovered. With the number of people with dementia growing each year, the lack of adequately validated diagnostic tools is a serious concern. Empirical investigations to further evaluate and validate screening instruments for cognitive impairment are necessary as we strive to develop effective treatments for all forms of this debilitating disorder.

Zoe Terpening BPsych(Hons), MSc, DClinNeuropsych · John R Hodges MD, FRCP, FMedSci · Nicholas J Cordato MB BS, PhD, FRACP

Reports of adverse events related to calcium supplementation should be supported by rigorous evidence Calcium is an essential nutrient, not only because of its major role in bone, where 99% of it is stored, but because of its central role in neuromuscular function. It is this latter role that explains why ionised calcium in the blood and tissue fluids is one of the most tightly controlled analytes of those that are commonly measured.1 However, maintenance of the calcium level in tissue fluids carries with it the penalty of continuous loss of calcium through the kidneys, bowel and skin, even on a low calcium intake, which is why the recommended daily calcium allowance for adults is relatively high, at 1000 mg.2 Nutritional deficiencies of other minerals, such as magnesium and phosphate, are rare because their tissue fluid levels are not tightly controlled but vary with intake and, therefore, so does their excretion. Calcium is different; reducing calcium intake has a marginal effect on extracellular calcium (and therefore on calcium excretion) because bone is mobilised to maintain the calcium level, which leads sooner or later to the development of osteoporosis. This is the case in laboratory animals3 and, by implication, in humans. Osteoporosis is therefore the index disease for calcium deficiency,4 just as rickets and osteomalacia are the index diseases for vitamin D deficiency; however, there is some overlap between them because the secondary hyperparathyroidism associated with hypovitaminosis D5 increases bone resorption. This is not to suggest that all adult osteoporosis is due to calcium deficiency, but simply to point out that the increase in bone resorption which follows menopause6 can be largely or wholly explained by the fall in calcium absorption and rise in obligatory calcium excretion which occur at this time,7 and also occur in oophorectomised animals.8,9 (The loss of a direct antiresorptive action of oestrogen on bone at menopause cannot be excluded but is probably quantitatively much less important.) For these reasons, it has become standard practice to recommend calcium supplementation to postmenopausal women, increasingly with vitamin D, to prevent or delay bone loss and reduce fracture risk. In the largest meta-analyses, calcium with vitamin D in adequate dosage reduces fracture risk by 25% or more, but vitamin D alone is not effective.10,11 Until very recently, calcium supplementation was not thought to cause any significant side effects. However, a New Zealand team recently reported an increase in the mean rate of mainly self-reported myocardial infarction in participants who were allocated to receive calcium supplements in five prospective trials for which patient-level information was available.12 Although the effect was not significant in any of the trials individually, it was significant at the 5% level in the whole series and has attracted sufficient media attention to endanger the use of calcium in the prevention of osteoporosis in postmenopausal women. An extension of this case against calcium recently appeared in this Journal, in a position statement on fracture prevention in aged-care facilities that was co-authored by one member of the New Zealand team.13 The article not only ignores the seminal work of Chapuy and colleagues on fracture prevention with vitamin D and calcium in aged care homes,14 but specifically opposes the general use of calcium supplementation on four separate grounds, none of which are directly referenced. The first is that long-term compliance with calcium supplementation is very poor, whereas in most trials it is not significantly different from compliance with placebo.15 The second is that the anti-fracture efficacy of calcium is marginal, despite overwhelming evidence to the contrary in the largest meta-analyses.10,11 The third is a bizarre claim that calcium could increase the rate of hip fracture; this is only supported by one trial (by one of the co-authors of the position statement) in which the adverse effect was not remotely significant in participants who complied with calcium supplementation,15 which is widely regarded as an anomaly and is contradicted by a later meta-analysis.16 The final is that calcium supplementation could increase the risk of myocardial infarction, which is highly contentious and negated by the latest meta-analysis of 17 trials.17 These negative statements about calcium (which are not reflected in the article’s abstract) are coupled with the promotion of bisphosphonates — particularly the intravenous variety — despite the fact that virtually all the bisphosphonate trials have incorporated calcium supplements. It may therefore be relevant that this article arose from a meeting financed by a pharmaceutical company that happens to market an intravenous bisphosphonate and gave some form of assistance to six of the 10 authors.13 Since it is clearly stated that this meeting was endorsed by the Royal Australian College of General Practitioners, the Australian and New Zealand Bone and Mineral Society and Osteoporosis Australia, there is a strong implication that these bodies also support the article itself. It is questionable whether such public bodies should lend their authority to a position statement of uneven quality and which runs the risk of being seen as commercially driven.

B E Christopher Nordin MD, FRACP, DSc

Timeliness is important only to the extent that high-quality patient care is preserved Increasing demand for emergency care has worsened access to acute hospital services across the developed world. Australia’s response has been a mixture of time-based emergency department (ED) targets to drive process improvements, efforts to divert patients from EDs into community-based services and changes to accelerate hospital-wide processes and patient discharges. There has also been increased investment in bed capacity, although not commensurate with rising demand. Seasonal planning has been undertaken for both acute and sub-acute sectors. Despite these initiatives, access to acute hospital care has become measurably worse.1 The Australian Government has announced the introduction of a 4-hour rule that guarantees all emergency patients access to a hospital bed within 4 hours of arrival if clinically appropriate; the target will apply to critically ill patients (triage category 1) by January 2011, and to all patients by January 2015.2 Almost simultaneously, the United Kingdom Government has announced that it will replace England’s 4-hour standard with measures of patient outcome and safety,3 designed to deliver continuous improvements in standards in EDs. A look at the experience in England and why the decision has now been taken to move away from a time-based standard may reveal lessons for Australia about how to implement its new rule. The 4-hour emergency access standard in England is different from the guarantee announced in Australia because it allows for fewer exceptions, requiring that all ED patients be admitted, transferred or discharged within 4 hours of arrival in the ED. It has been in place for nearly 10 years, with a 98% operational threshold since 2003 to allow for the small number of patients who need more than 4 hours of ED care. Despite some obvious attempts at gaming and data manipulation,4 it has genuinely reduced length of stay overall in EDs and won patients’ approval.5 Before the introduction of the standard, there was evidence of patients having long waits in EDs before being seen by a doctor and before being transferred to a ward. The causes of delays were variable between hospitals.6 Also as a direct consequence of the 4-hour standard, innovations7 to manage patient care more efficiently have been introduced, including new models of care (eg, clinical decision units to fast-track care of patients with minor injuries). However, initiatives to reduce ED attendances have had little success. In fact, they may have led to poor practice in some hospitals, such as premature discharge and transfer of patients from the ED, resulting in preventable deterioration and mortality.8 Investment in the UK National Health Service (NHS) has doubled in recent years,9 with increased hospital staffing and capacity, increased resourcing of EDs and increased investment in community social care. The 4-hour standard has been the single major performance measure of the processes of the UK’s emergency care system. NHS organisations were strongly performance managed against this standard, with penalties for not achieving it. Hence, a lot of effort was expended to meet the target. In most EDs, accurate data collection systems are now in place to track patients, but are not necessarily available throughout the rest of the patient journey. Research has shown a link between length of stay in the ED and various outcomes, but it is not known whether overall patient outcomes have improved or deteriorated as a result of the 4-hour target. The Mid Staffordshire Trust review10 found that an excessive focus on time-based targets caused a significant increase in patient mortality and a major outbreak of hospital-acquired infection. But an independent report from Harvard University found “no evidence for any of the dysfunctional effects”.11 A recent Nuffield Trust report5 suggested that the emphasis on time in EDs had resulted in increased referral of patients between agencies, but no real improvement in efficiency and possible decline in efficiency. The over-focus on time-based medicine may result in work dissatisfaction for staff and decreased training opportunities. Additionally, the patient contact time may be reduced or hurried, potentially decreasing both patient and doctor satisfaction. The evolving approach in England aligns to the incoming UK coalition government’s commitment to freeing the NHS from what it sees as unnecessary micro-management through the imposition of process targets. Its more holistic approach is to hold the NHS to account for clinical outcomes and the quality of patients’ experiences, and to allow local decisions on processes and structure; results of a dashboard of clinical quality indicators will be published to encourage continuous improvement. Nevertheless, the UK Government recognises the clinical importance of timeliness of care and has said that it will include it in the dashboard of indicators. The lesson for Australia is that although introduction of a rigid time-based target to empty EDs is seductively simple and potentially effective in solving a single problem, there are significant dangers. Measurement systems should be in place to ensure that patient safety and quality of care are not compromised at any stage of the emergency care pathway. This requires a significant investment in information technology and highly developed monitoring of patient care processes and outcomes, including national registries for high-risk, high-cost patients and national audits of important standards of care. Clinicians in both countries agree that best care combines optimal outcome, patient experience and timeliness, and involves looking at the whole emergency care pathway from the first call for help until return home.

Peter A Cameron MD, FACEM · Matthew W Cooke PhD, FCEM, DipIMC

Independent advice continues to be vital for maintaining standards in medical training Many younger doctors may have trouble believing it was only 25 years ago that the assessment of Australian medical schools (for the purpose of medical registration in Australia) changed from assessment by the General Medical Council of the United Kingdom to assessment by a local independent authority. In 1985, the accreditation process was transferred to Australia, and the Australian Medical Council (AMC) was established. The AMC recently marked its first 25 years by publishing its history, Assuring medical standards: the Australian Medical Council 1985–2010.1 The book catalogues many impressive achievements and also describes in detail some significant obstacles in the Council’s progress. Australia now has an almost seamless accreditation process for all phases of medical education (medical student education, postgraduate training and, through the medical colleges, continuing medical education) that is envied by other nations. In addition, the AMC has established a reputation internationally as a leader in the assessment of international medical graduates and for its work in supporting them in preparing for assessment. The release of the AMC history coincides with the most significant change in the regulation of the health professions since laws for registration were first enacted in the mid 19th century.2 It is timely to consider the lessons from the AMC’s experience as we enter this new era of national registration, and to reflect on the importance of independence in setting standards for the profession in the future. Medical education and medical practice are moving into uncertain territory. Several critical issues are likely to engage the AMC and others involved in medical education in the immediate future. First and foremost is securing appropriate clinical training for the rapidly increasing numbers of medical students and graduates, and ensuring sustainable funding for that training through the state and national bodies that have responsibility for the health workforce and clinical training. There is also an urgent need to consolidate state-based standards for early graduate training (the first two postgraduate years) and to align them with those for medical schools and specialty training. The present interest in the ill-defined “competency-based training” is stimulating attempts to define competencies more precisely. If this leads to job redesign and task substitution (as envisaged by the Productivity Commission),3 then that will need to be done in a measured and intelligent manner which does not diminish existing standards of medical care. There is an urgent need to rethink teaching about patient safety throughout medical education.4 If we are ultimately to ensure that preventable harm to patients becomes negligible, then the new science of patient safety must have a high priority in the training and professional development of all doctors.5 The AMC is considering whether this will require strengthening of its accreditation standards. These matters all rest on the underlying responsibility of medical educators to develop good students into competent doctors who will maintain their knowledge, skills and professionalism throughout their careers. Regulation of the medical profession was originally intended to protect the community by defining a legally qualified medical practitioner, but health workforce supply now occupies a pre-eminent place in the new national regulatory structure. Sections 11(3)(d) and 11(4)(a) of the Health Practitioner Regulation National Law Act 2009 (Qld) provide for the Ministerial Council to intervene in an accreditation standard when that standard might impact on the recruitment or supply of medical practitioners. Before the legislation was passed, a caveat was added by way of section 11(4)(b) requiring the Ministerial Council to consider the impact of any such intervention on the quality and safety of health care. While the national law thus incorporates the tension between workforce considerations and standards of medical education, this represents potential future conflict. The concurrent reforms in funding of clinical training have the potential for a more immediate impact on medical education. The need to account for the appropriate expenditure of funds may see a push towards standardisation of clinical training — “one size fits all” thinking — supported by an education model built on “tick box” competencies. Comprehensive, thorough clinical training is essential for developing an effective, flexible and safe medical workforce, and for producing practitioners able to adapt to changes in medical sciences and clinical practice throughout their careers. It would be reassuring for the medical profession if we could confidently predict that the AMC will still be here after the next 25 years, but this is by no means certain. For medicine, it is vital that the AMC commits itself to working closely with the bodies whose responsibilities will influence standards of medical education and medical practice, including the Medical Board of Australia, Australian Health Practitioner Regulation Agency, and Health Workforce Australia. It is equally important, given the policy focus on health workforce reform, that the AMC continues to provide strongly independent, evidence-based advice and guidance on standards of medical training and assessment.

Richard A Smallwood AO, FRACP, FRCP · Ian Frank BA · Theanne Walters BA

The Australian Government’s recent decision not to renew federal funding for the Master of Applied Epidemiology (MAE) program at the Australian National University (ANU) puts the nation’s public health response capacity at serious risk. This program has provided the investigative backbone to the Communicable Diseases Network Australia for nearly 20 years. A charitable view is that its disestablishment came about as an administrative accident — collateral damage when Cabinet decided to terminate the much larger Public Health Education and Research Program (PHERP) after a 20-year funding cycle had reached its promised end. Funding for the MAE was rolled into the PHERP quite recently as an administrative convenience, after being supported through a distinct funding stream for most of its life, but the two are in fact very different types of public health activity. Although other PHERP-funded courses are traditional campus-based degree programs, the MAE puts its intake of outstanding health professionals through intensive field apprenticeships as disease detectives. Over 2 years, trainees undertake brief campus-based training blocks, but, for most of their time, they are placed at health agencies around the nation where they are immersed in disease surveillance and outbreak investigations. They serve as a flying squad to respond at short notice to unusual infectious disease events that present potential threats to the population’s health.1 The program has been a bargain for the government, with a budget under $2 million per year (the cost of about six tertiary hospital beds), which meets trainees’ stipends and supports a small team of academic supervisors. Over two decades, 160 MAE trainees have played central roles in stemming the spread of about 200 epidemics, including severe acute respiratory syndrome (SARS), pandemic (H1N1) 2009 influenza, Hendra virus, food-borne infections, and many others. Their work has generated over 500 academic publications, often of national and global public health significance.2-4 The program was originally modelled on the world-renowned Epidemic Intelligence Service at the Centers for Disease Control and Prevention (CDC) in the United States. The Australian MAE has helped spawn equivalent programs in China, India, Indonesia and Malaysia. In addition to serving as a standing national response team during their 2-year apprenticeship, graduates of the MAE program have gone on to become national, and in some cases international, leaders in public health. The employment distribution of 104 non-Indigenous graduates who completed a survey recently is shown in the Box. The MAE has a particular emphasis on supporting Aboriginal and Torres Strait Islander trainees, recognising that the burden of infectious diseases in Australia falls disproportionately on the Indigenous population. Placements have been made in settings that have allowed Aboriginal trainees to work closely with Aboriginal communities. Twenty-seven Aboriginal MAE graduates have gone on to make a unique contribution to several areas of Aboriginal health and have become role models for Aboriginal health research in Australia.5 Thirteen of these have used their training in this program as a portal of entry to PhD candidacy. A review of the program commissioned jointly by the Australian Government and ANU in February 2010 was unequivocal in recommending that it should continue as a key element of Australia’s disease control activity.6 The MAE program was born as a response to the urgent need, recognised during the early years of the HIV epidemic, for Australia to upgrade its national disease intelligence capacity. It was initiated with assistance from the US CDC, and its first Australian Director was the late Professor Aileen Plant, who would be appalled at its disappearance with no apparent replacement in sight. This will leave Australia vulnerable at a time when increasing population movements, changing climate and other pressures increase the likelihood that we will face new pandemics and the re-emergence of old ones.7 Although Australia is now one of few industrialised nations that has no national centre for disease control, the MAE program at least represented one of the essential elements that such a national organisation would provide.1 Infections respect neither state nor national boundaries, and under Australia’s political structure their control can only be achieved through a consistent, coordinated effort by the federal and jurisdictional governments. The ongoing human resource represented by the MAE trainees is a highly cost-effective insurance policy that we cannot risk losing in the challenging times ahead. Non-Indigenous Master of Applied Epidemiology graduates by current employer and type of work, 1991–2010 Employment classification Institution Epidemiologist Other public health Policy advisor Academic Other research Clinician Laboratory Total Federal government 6 — — — — — — 6 State government 22 9 2 — 1 — 1 35 Research institute 11 — — 3 2 — — 16* International health organisation 7 2 2 — 1 — 1 13† Non-government organisation 2 — 2 — — — — 4 Private enterprise — 1 1 — — 2 — 4 Hospital 1 — — — — 5 — 6 University 4 — — 16 — — — 20 Total 53 12 7 19 4 7 2 104‡ — = zero or not applicable. * Eight of the current jobs are at research institutes that provide services to government in communicable disease surveillance. † Ten of the current jobs are with the World Health Organization. ‡ Twenty-nine students did not complete the survey.

Robert M Douglas MD, FRACP, FAFPHM · Fiona J Stanley MD, MSc, FAFPHM · A Rob Moodie MB BS, MPH, FAFPHM · Anthony I Adams MB BS, MPH, FAFPHM · John M Kaldor PhD

Passive surveillance cannot be relied on as the sole means of surveillance On 22 April 2010, use of seasonal trivalent influenza vaccine in children aged 5 years and under was suspended across Australia, pending an investigation into an apparent increase in reports of adverse events following immunisation (AEFI).1 This unprecedented halt to a national immunisation initiative followed Western Australia’s decision to place a moratorium on the use of this vaccine in young children after observing a spike in emergency department presentations for high fever and febrile convulsions after vaccination.2 A subsequent investigation by the Therapeutic Goods Administration indicated that febrile convulsions related to the vaccine were reported from all jurisdictions except the Northern Territory.2 The apparent rate of febrile convulsions following vaccination was 5–9 per 1000 doses administered, about 50 times higher than that reported following measles–mumps–rubella vaccination.2,3 A recent review, requested by the Minister for Health in WA, has highlighted significant deficiencies in AEFI surveillance.4 In Australia, the current mechanism for identifying AEFI nationally is passive surveillance. Passive surveillance relies on health providers and the public recognising and reporting suspected AEFI to state or federal health authorities. The constraints that are inherent to passive surveillance, including under-reporting and biased reporting, are compounded by the diverse approaches to surveillance that are employed throughout Australia, as illustrated by a fourfold difference in AEFI reporting rates per 100 000 population between jurisdictions.5,6 Adding to concerns about variable sensitivity across the state systems is the inevitable delay in collection, aggregation and analysis of AEFI reports forwarded to the national authority. A number of the issues evident during the response to the vaccine-associated reactions were recognised 5 years earlier during the National Vaccine Safety Workshop.7 A clear set of recommendations for improving adverse event surveillance was identified at the time, but many of the recommendations have not been adequately addressed. Robust postmarketing surveillance is vital for influenza vaccines because seasonal trivalent influenza vaccine does not require clinical trial data to demonstrate safety before release — it is assumed that safety is not altered by the annual change in the combination of vaccine strains. While past experience suggests that this is true, history also indicates that future vaccine scares are inevitable and we should plan accordingly.8 Trivalent influenza vaccine, in particular, highlights the need for postmarketing surveillance to be linked with the capacity for rapid review and response, because a large proportion of the vaccine is administered over a short period before the onset of the influenza season each year. The way forward is to establish a coordinated, uniform approach to AEFI reporting, coding, collation and analysis. A standing vaccine safety monitoring group which includes key stakeholders — representing the regulators, state and national immunisation programs and vaccine safety and epidemiology experts — needs to be urgently established. The inability of the existing surveillance systems to detect the early signal of an increased incidence of febrile convulsions, within 24 hours of receiving 2010 seasonal trivalent influenza vaccine, demonstrates that passive surveillance cannot be relied on as the sole means of surveillance. Complementary active surveillance systems which can methodically detect potential AEFI signals, quickly establish rates and establish causality should be developed. The Australian Childhood Immunisation Register is uniquely placed to contribute to vaccine safety surveillance through data linkage with hospital morbidity and emergency department datasets, as demonstrated by a recent study from South Australia.3 Sentinel surveillance in four tertiary care Australian paediatric hospitals has been shown to be an effective mechanism of surveillance for specific AEFI.9 Implementing active AEFI surveillance systems will require sustainable funding, but this will be a small fraction of the cost expended on vaccines and vaccine delivery and could be resourced by levying a surcharge per vaccine dose sold, similar to methods adopted elsewhere to support compensation for vaccine-associated injuries.10 Central to any system of vaccine safety monitoring are issues of governance; specifically, transparency in decision making. Other countries currently provide full disclosure and web access to de-identified AEFI reports and open access to the deliberations of expert committees.11,12 This engenders public trust in immunisation programs, and similar strategies should be considered in Australia. The vast majority of Australian parents, vaccine recipients and health care providers trust public health authorities to assess and monitor vaccine safety. This is critical to ensure that the benefits of vaccination outweigh any potential risks. In the aftermath of the 2010 seasonal trivalent influenza vaccine experience, maintaining the public’s trust requires that we get started on building the fully functional, standard-of-care AEFI surveillance system that Australia deserves. Vaccine safety should be an integral component of the National Immunisation Strategy, which should include strategies for comprehensive and complementary passive and active systems of surveillance.

Michael S Gold MB ChB, MD, FRACP · Paul Effler MD, MPH · Heath Kelly BSc, MB BS, MPH · Peter C Richmond MB BS, MRCP, FRACP · Jim P Buttery MB BS, FRACP, MSc

There is still room for improvement, both in decreasing delays in, and deciding who is eligible for, reperfusion therapy In patients with acute ST-segment-elevation myocardial infarction (STEMI), early coronary reperfusion — within 1 to 2 hours of symptom onset — by either thrombolysis or primary percutaneous coronary intervention (PCI) reduces the mortality rate by half. However, this benefit quickly dissipates with further delay in treatment.1 As “time is muscle”, it is the time from symptom onset to reperfusion (or total ischaemic time), rather than the mode of reperfusion, that is the critical determinant of outcome. Hence the imperative to minimise: (i) delay by patients in recognising symptoms as possible myocardial infarction (MI) and seeking medical help; (ii) delay in ambulances responding to calls; (iii) delays in diagnosing STEMI on first medical contact; and (iv) omissions or delays in administering the most appropriate means of reperfusion in eligible patients. In this issue of the Journal, Huynh and colleagues, using data from a prospective Australian registry, report on processes of care and outcomes of 755 patients presenting with suspected STEMI.2 There is good and bad news in this report. The good news is that the median time from symptom onset to first medical contact in this cohort was 105 minutes (1.75 hours) compared with 3.2 hours for patients with undifferentiated chest pain, reported in 2005.3 If the sample in the study by Huynh and colleagues2 is representative of most patients with MI, this suggests that public recognition of warning symptoms and the need to seek medical help urgently has improved over the past 15 years in response to public education campaigns that target individuals at high risk and behavioural barriers to action.4 Reperfusion reduced mortality at 12 months (adjusted for baseline risk as calculated using the Global Registry of Acute Coronary Events [GRACE] risk score) by 65% (and by 78% if administered in a timely fashion), similar to results noted in recent overseas observational studies that used similar risk-adjustment methods.5 Finally, there was no difference between metropolitan and rural patients in the time to presentation or the proportions of patients who received reperfusion therapy, or who received it in a timely manner, and the same applied to inhospital and 12-month mortality rates. This suggests the “city–bush” gap in coronary care noted in past studies6 is being closed, although more rural patients (74%) received thrombolysis, while more metropolitan patients (68%) received primary PCI. The bad news is that one in three patients did not receive any form of reperfusion — a figure common to other countries and which has proven resistant to change.7 Unfortunately, contraindications to either form of reperfusion in individual patients were not reported, but contraindications and patient refusal have been reported to account for no more than 10% of all patients with STEMI.8 This means just over one in five patients were likely to have been eligible for reperfusion therapy but failed to receive it. Factors associated with not receiving reperfusion therapy on regression analysis included a past history of diabetes or documented coronary stenoses on angiography, acute pulmonary oedema on presentation, left bundle branch block on electrocardiogram (ECG), and a non-cardiologist as the treating doctor. In other studies of patients eligible for reperfusion therapy, additional factors have included older age, admission to a facility not capable of performing PCI, increasing time to presentation, renal insufficiency, prior stroke or coronary artery bypass grafting, being female, and presentation without chest pain or with an equivocal ECG.5,7 Some of these associations reflect diagnostic uncertainty in patients with atypical clinical presentations and non-diagnostic ECGs or clinician concern about the risk of bleeding in older patients (especially underweight women) and those with renal failure or prior stroke. However, registry data show that in this patient group at relatively high risk, early reperfusion therapy compared with no reperfusion reduces inhospital mortality by 38%, with primary PCI being more effective than thrombolysis.9 Clinicians may need to recalibrate their perceptions of benefit and risk in groups of patients who have often been excluded from clinical trials. The other bad news is that among patients receiving reperfusion therapy in the study by Huynh and colleagues (61%, primary PCI; 37%, thrombolysis), only one in three received it within an optimal time frame.2 The median door-to-needle time (D2N) for thrombolysis was 43 minutes (versus a 30-minute standard) and door-to-balloon time (D2B) for primary PCI was 102 minutes (versus a 90-minute standard). These times are longer than those reported in contemporary cohorts in other developed countries, such as 33 minutes D2N and 83 minutes D2B in a Canadian cohort,5 and 30 minutes D2N and 86 minutes D2B in the GRACE international registry.10 Attention has recently shifted to reducing total system delay, defined as the time from first contact with the health care system (ie, ambulance) to initiation of reperfusion therapy, which now appears to be more strongly associated with mortality than patient delay in seeking care.11 In reducing system delay, the timing of PCI (immediate v delayed v rescue) and its relation to thrombolysis in patients presenting to non-PCI-capable hospitals becomes a pivotal issue. Current Australian and New Zealand guidelines state that fibrinolysis is preferred to primary PCI in patients presenting within 1 hour of symptom onset unless balloon insufflation can occur within 60 minutes after first medical contact (in most cases, this is patient pick-up by ambulance).12 In patients presenting between 1 and 3 hours after symptom onset, fibrinolysis is preferred unless primary PCI can occur within 90 minutes of first medical contact. Studies show that in patients with symptom onset of less than 3 hours and for whom transfer to PCI-capable hospitals would delay primary PCI for more than 90 minutes, the combination of early lysis and aggressive use of rescue PCI (in the third of patients with persistent ST-segment elevation, cardiogenic shock, severe heart failure or serious ventricular arrhythmias) confers comparable outcomes with that achieved with primary PCI.13 In this regard, prehospital thrombolysis undertaken by ambulance paramedics, combined with early PCI where appropriate, seems to be an underused strategy in reducing system delay.14 Another issue is the role of risk stratification in deciding who should receive which form of reperfusion. A treatment-risk paradox is often seen whereby eligible patients at high absolute risk of death or recurrent MI are less likely to receive reperfusion therapy (for reasons already mentioned) than those at lower risk9 and in whom treatment delays attenuate the absolute benefit of reperfusion to a greater degree. In considering transferring patients presenting within 6 hours of symptom onset for primary PCI, the higher the risk profile, the larger the reduction in mortality benefit with primary PCI compared with thrombolysis for each 10-minute increase in PCI-related time delay.15 Delays must be minimised in high-risk patients, rather than simply working to a 60-minute or 90-minute D2B rule. The equipoint between primary PCI and fibrinolysis (the PCI-related time delay at which primary PCI loses its superiority in terms of mortality benefit compared with fibrinolysis) may be as little as a D2B time of 40 minutes in a high-risk situation (such as a young patient presenting early with a large anterior infarction) versus 179 minutes in lower risk situations (such as an older patient presenting late with a non-anterior infarction).16 Several strategies have been shown in both Australian and overseas studies to be effective in reducing total ischaemic time (Box),17-19 and these need to become mainstream care. This will require a multifaceted approach involving educating both patients and doctors; coordinating ambulance, emergency department and cardiac catheterisation laboratory components of care; establishing integrated networks of non-PCI and PCI-capable hospitals with decision support and transfer processes that take patient risk and time to presentation into account; and ongoing data collection and feedback within clinical registries. Strategies for decreasing delays in reperfusion therapy Hospital-based strategy Potential tools Prehospital ECG and field assessment by paramedics Prehospital ECG policy Guidelines for field assessment with electronic transmission to, and verification of ECG diagnosis by, emergency department staff Prehospital thrombolysis for patients who are within 1 hour of symptom onset Training of paramedics in ECG diagnosis and administration of thrombolytic agents Transfer of PCI-eligible patients direct to a PCI-capable facility Pre-destination protocol for paramedics Rapid assessment and ECG on patients presenting to emergency departments with chest pain Dedicated chest pain cubicles in emergency departments with ECGs taken within 10 minutes of arrival Rapid management of diagnostically uncertain cases Formal order sets for suspected myocardial infarction in cases of initially non-diagnostic ECG Rapid initiation of thrombolysis in eligible patients Formal thrombolysis protocols that can be initiated by emergency department nurses or physicians without consulting the cardiology department Emergency department bypass of PCI-eligible patients with direct transfer to a catheterisation laboratory Prehospital (or first hospital) assessment policy Guidelines for direct activation of the catheterisation laboratory by emergency department staff without review or approval by cardiologists Single-call activation of the catheterisation laboratory team Alert system with single person as contact (senior registrar or consultant) Catheterisation team fully operational within 30 minutes of activation Staff policy and roster Performance of PCI 7 days a week, 24 hours per day Clearance of elective cases; maintained availability of ready-to-go equipment and staff Prompt data feedback Time-entry forms for door-to-needle and door-to-balloon times, and these times notified to all team members after each procedure Team-based approach Team training program; limited handovers with single team approach Regionalised “hub-and-spoke” hospital networks which expedite patient transfer to PCI-capable facility Triage and expedited transfer guidelines for referring and receiving hospitals PCI = percutaneous coronary intervention. ECG=electrocardiogram.

Ian A Scott FRACP, MHA, MEd

Providing world-class stroke care in Australia Cerebrovascular disease is the third leading cause of disease burden in developed nations, and is predicted to be the fourth ranked disease burden worldwide by 2030 after unipolar depressive disorders, ischaemic heart disease and trauma.1 All of these conditions are characterised by sudden and unpredictable demands requiring an immediately accessible, systemised and multidisciplinary approach to care. The complexities of acute ischaemic stroke in Australia have been addressed by detailed clinical guidelines.2 An emergency care bundle for stroke and transient ischaemic attack has recently been offered by the National Institute of Clinical Studies of the National Health and Medical Research Council.3 When administered to appropriate patients within 3 hours of stroke symptom onset, the benefits of recombinant tissue plasminogen activator (rt-PA) are significant, with treated patients 30% more likely to be in the excellent outcome grade — an absolute increase of 13%4 — and improvements in modified Rankin scores for some other patients with higher modified Rankin scores. The number of patients needed to treat for benefit may be as low as three.5 The associated risk of an intracerebral haematoma causing deterioration is about one in 30.5 The third European Cooperative Acute Stroke Study (ECASS3), a randomised trial of intravenous rt-PA in the 3–4.5 hour window, demonstrated a smaller but statistically significant benefit with no increase in haematoma rate.6 A recent Cochrane review of 26 thrombolysis trials of rt-PA, streptokinase, desmoteplase, urokinase and pro-urokinase, which included 7125 patients, found a significant net benefit in terms of death and dependency.7 The clinical applicability of new therapies may be exaggerated by the Hawthorne effect of clinical trials. The European Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST) registry — a mandated requirement of European drug licensing authorities — was established to monitor thrombolysis in day-to-day clinical practice.8 It included centres not experienced with thrombolysis and demonstrated the feasibility and safety of thrombolytic therapy across Europe. The cover of the issue of The Lancet in which the registry outcomes were published declared that rt-PA is “safe and effective in routine clinical use”. The rate of symptomatic intracerebral haemorrhage (ICH), as defined by the National Institute of Neurological Disorders and Stroke (NINDS), was 7.3% in SITS-MOST for both experienced and new thrombolysis centres, with a calculated mortality rate from ICH at 3 months of 1.9%.8 Early deterioration due to ICH in the SITS-MOST registry occurred in 1.7% of cases. In this issue of the Journal, Simpson and colleagues report the Australian contribution to the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR),9 reflecting the local experience of treating acute stroke 15 years on from the NINDS trial.4 Participation in the Australian component of the SITS-ISTR was voluntary. Many centres undertaking thrombolysis did not participate, and this may weaken the generalisability of this new data. Nevertheless, over 500 patients were enrolled and outcomes did not differ from those of the larger international database. The important safety data were reassuring, with a symptomatic ICH rate of 8.3% by the definition used in the NINDS randomised controlled trial, and 1.3% by the SITS-MOST definition. The 3-month ICH mortality rate was 2.2%. A British subset of SITS has been reported recently, with outcomes also comparable to those for the rest of Europe.10 In the SITS-MOST registry, new and experienced centres did not differ in terms of their haemorrhagic complication rates.8 While the Australian report by Simpson et al does not detail information regarding the types of centres involved, implementation of thrombolysis in Australia beyond the centres that participated in the thrombolysis trials is already well established. Audits by the National Stroke Foundation have found that 33 hospitals were regularly treating with rt-PA in 2007,11 and that this increased to 50 by 2009.12 New metropolitan and rural centres can adopt thrombolysis with executive support and leadership from medical and nursing “stroke champions”. This nearly always results in the establishment of a stroke unit and the adoption of a local thrombolysis protocol with coordination of the prehospital emergency services. Mentorships with established metropolitan centres are worthwhile in the early stages. Some direct links using telemedicine for the treatment of the first cases have been employed in Victoria (Associate Professor Bernard Yan, Neurologist and Neurointerventionist, Royal Melbourne Hospital, personal communication). Early recognition and intervention for stroke requires a tightly coordinated interdisciplinary approach and rates of intravenous thrombolysis administration can be used as a clinical quality indicator for stroke care.13 Ongoing participation in the SITS-ISTR and the Australian Stroke Clinical Registry is crucial for monitoring the progress of this important therapy. A coordinated system of care for stroke and transient ischaemic attack in Australia has been stalled by the lack of a concerted effort to adopt thrombolysis. Australian registry data provide reassurance that Australian stroke physicians, emergency physicians and systems that support thrombolysis can achieve similar results to those recorded in Europe. We can now move beyond discussing the efficacy and feasibility of implementing this therapy and work toward a more coordinated system of applying the evidence.

Mark Fitzgerald MB BS, FACEM · Richard P Gerraty MD, FRACP

Carotid artery stenting has a place in managing symptomatic stenosis, but only sometimes Carotid stenosis remains one of the most readily treatable causes of ischaemic stroke. Its treatment has undergone many changes in recent years, with the advent of endovascular techniques seeming to offer great promise of a much less invasive procedure. In the late 1990s, the Australian Association of Neurologists published guidelines for the use of carotid balloon angioplasty alone (ie, without stenting) as a treatment for carotid stenosis, recommending cautious use in the absence of data from randomised controlled trials (RCTs).1 However, advances in vascular stent technology have resulted in a greatly increased use of carotid artery stenting (stenting), often with specialised filter devices deployed distal to the carotid stenosis to catch embolic debris that may arise from catheter or stent manipulation. Recent evidence from RCTs has cast doubt on the safety of widespread use of stenting for the treatment of patients with symptomatic or asymptomatic carotid stenosis. The overall results from these RCTs indicate that carotid endarterectomy (endarterectomy) is still the preferred treatment option for symptomatic carotid stenosis. The results of three major European studies into the treatment of symptomatic stenosis — Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S); Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE); International Carotid Stenting Study (ICSS) — showed that stenting was more hazardous than endarterectomy for the outcomes of stroke and death during the periprocedural period (30 days), and on longer-term follow-up.2-4 Perhaps in contrast, the recent North American Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) demonstrated equivalent (non-significant) rates of stroke, myocardial infarction and death in its stenting and endarterectomy groups in the periprocedural period, and at 4 years.5 However, in CREST there was a significantly reduced rate of stroke and death in the endarterectomy group, but this was offset by an increased risk of myocardial infarction, in part due to the definition of myocardial infarction used, and a greater number of study patients with comorbid ischaemic heart disease.5 Use of cerebral protection devices during stenting was mandated in CREST but not in the European studies. The value of these devices is in question, with evidence indicating that they were no more effective in reducing the clinical risk of stroke than unprotected stenting.6,7 Moreover, data from a magnetic resonance imaging substudy undertaken as part of the ICSS indicated that, compared with endarterectomy, there was a threefold increase in silent brain infarctions in stenting with use of cerebral protection devices (adjusted odds ratio, 3.28 [95% CI, 1.5–7.2]).7 A meta-analysis of 11 RCTs (including EVA-3S, SPACE and ICSS, but not CREST) showed that endarterectomy was superior to stenting in short-term but possibly not longer-term outcomes, a difference largely driven by non-disabling stroke.8 The Australasian guidelines9,10 have now been upgraded following additional published data from CREST5 and a meta-analysis of the three large European trials (EVA-3S, SPACE, ICSS)11 indicating that stenting is at least as safe as endarterectomy in patients under 70 years of age, while it presents a greater risk of stroke for those older than 70 years (Box). The RCTs indicate that there is currently no clear evidence to support either endarterectomy or stenting as a treatment for asymptomatic carotid stenosis. Indeed, current medical therapies have reduced the risk of stroke in asymptomatic stenosis to as low as 0.5% per year.12 Ongoing RCTs continue to address this question (eg, the Asymptomatic Carotid Surgery Trial 2, comparing stenting and endarterectomy in the treatment of asymptomatic carotid stenosis).13 Until recently, in Australia and New Zealand, there were no specific published guidelines for carotid artery stenting. To redress this, an intercollegiate working group was formed — the Carotid Stenting Guidelines Committee — comprising expert representatives of the Royal Australasian College of Physicians, the Royal Australasian College of Surgeons, and the Royal Australian and New Zealand College of Radiologists. Consensus for guideline parameters was reached using the modified Delphi consensus method of iterative consultation. The committee’s guidelines recommend clinical selection criteria for carotid artery stenting, as well as cognitive and technical requirements that clinicians should meet before performing stenting.9,10 The guidelines do not deal with training criteria and procedural accreditation as these are determined by the Conjoint Committee for Recognition of Training in Peripheral Endovascular Therapy of the abovementioned colleges. On current evidence, the guidelines recommend that carotid artery stenting may be considered a treatment option in specific, high-risk patients with symptomatic severe stenosis who are considered unsuitable for endarterectomy (Box).10 It is important to note that these are relative contraindications to endarterectomy as there is no evidence to support stenting in these patients (indeed, they are often excluded from clinical trials). Finally, it is important that all patients being considered for a carotid intervention have preprocedural neuroimaging and independent neurological assessment before and after the procedure. This allows for an audit comparison with the results of RCTs where neurological evaluation of all patients is routine, and serves as a benchmark for best clinical practice. In summary, the evidence from RCTs indicates that, at present, a cautious approach should be taken to recommending carotid artery stenting — festina lente (hasten slowly). Stenting should not be performed in most patients with symptomatic severe carotid stenosis, and there is currently no evidence to support stenting as a treatment for asymptomatic carotid stenosis. Stenting warrants consideration in younger patients (< 70 years of age) and those with symptomatic severe carotid stenosis unsuitable for endarterectomy. These standards should apply in all health care settings, public and private. Advances in endovascular technologies, and evidence from future RCTs and meta-analyses, will guide revisions of the guidelines. Carotid Stenting Guidelines Committee: recommended indications and contraindications for carotid artery stenting (CAS)10 Indications Symptomatic carotid disease in the following conditions may be assessed at high surgical risk for carotid endarterectomy (CEA) by an appropriate clinician experienced in the management of carotid stenosis: post-radiation therapy block dissection of the neck in-situ tracheostomy recurrent stenosis following previous CEA severe cervical spine arthritis surgically inaccessible carotid stenosis (eg, obesity, high carotid bifurcation) contralateral recurrent laryngeal nerve injury contralateral internal carotid artery occlusion Symptomatic severe carotid stenosis* in patients under 70 years of age, where carotid revascularisation is considered appropriate Symptomatic or asymptomatic carotid stenosis where carotid revascularisation is considered appropriate, and the patient is randomised to CAS in a clinical trial Contraindications Absolute Carotid stenosis in a patient with significant contraindications to angiography Carotid stenosis with angiographically visible intraluminal thrombus Carotid occlusion Relative Carotid stenosis associated with an intracranial vascular malformation Contraindications related to vascular anatomy and atherosclerosis (eg, type 2–3 arch; bovine arch; severe aortic arch or ipsilateral common carotid atherosclerosis; severe proximal common carotid artery tortuosity; severe distal internal carotid artery tortuosity (possibly compromising embolic protection devices); sharply angulated internal carotid artery; carotid string sign; circumferential calcification of carotid plaque; loose thrombus associated with carotid plaque) * Severe carotoid stenosis is defined as ≥ 70% using North American Symptomatic Cartoid Endarterectomy Trial criteria.5

on behalf of the Carotid Stenting Guidelines Committee (Australia and New Zealand)

Results of two new trials will drive further research into the “andropause hypothesis” Two important research articles, published in a recent issue of the New England Journal of Medicine (NEJM), bracket the topic of prescribing testosterone for older men.1,2 Testosterone treatment for older men is based on considering male ageing as analogous to either menopause or pathologically based hypogonadism. The former is a false analogy — menopause has a unique natural history featuring complete failure of female reproductive hormones in mid-adult life, contrary to all other human hormonal systems which decline gradually and modestly with ageing. The latter is based on the superficial resemblance of non-specific symptoms in ageing men with those of most hormonal deficiencies or chronic diseases. This “andropause hypothesis” is not well substantiated, with the 2004 United States Institute of Medicine’s authoritative review3 concluding that available evidence did not justify a major study of testosterone replacement in older men comparable to the Women’s Health Initiative (WHI) study of oestrogen replacement in menopause. Nevertheless, the past two decades have seen an approximately 20-fold increase in testosterone prescribing despite no proven new indications. This is largely confined to the US, with minimal changes in Australia4 and other regional markets; however, that bandwagon could certainly be viewed as having left the station, fuelled by heavy direct-to-public drug advertising in the US. One of the NEJM articles reports the European Male Ageing Study (EMAS) — a large observational study of male ageing involving more than 3300 men aged 40 years and over from population-based sources in eight European cities, and the European counterpart to the seminal Massachusetts Male Ageing Study (MMAS).1 The EMAS evaluated the relationship of non-specific physical and mental symptoms to serum testosterone levels, an approach originating from clinic-based studies5,6 and used in the analysis of the population-based data of the MMAS,7 to which the EMAS adds a large sample size. Crucially, the statistical power of this study can neither overcome its logical flaws nor the inconsistency between its findings and conclusions. After noting statistically insignificant associations of low testosterone levels with clinically relevant physical or psychological features, the researchers focus on three sexual symptoms — erectile dysfunction, frequency of morning erections and sexual desire. Each symptom shows a weak association with serum testosterone levels, featuring a shallow breakpoint (at levels of 8–11 nmol/L) together with high false-positive and negative rates. Although the only consistent significant association is between all three sexual symptoms and a serum testosterone level threshold of 8 nmol/L, the researchers inexplicably propose a “definition” of “late-onset hypogonadism” requiring the presence of all three sexual symptoms plus a serum testosterone level of less than 11 nmol/L. The proposal is further undermined by the study’s findings that all the associations of the three sexual symptoms with low serum testosterone levels are nullified by adjustment for age, obesity and co-existing illnesses, indicating that they are attributable to confounding rather than any authentic correlation. The study’s authors, in effect, overinterpret cross-sectional data to imply causality. Such quasi-longitudinal interpretation is especially unsafe when blood test results are not steady for the population. This is the case for serum testosterone, with evidence of downward temporal trends in America and Europe,8 probably due to progressive population increases in obesity. The impact of implied causality should not be underestimated — despite its ritual caveats against testosterone prescribing, this article is likely to encourage more overuse of testosterone. The article resonates with past mistakes, notably the decades of excessive oestrogen prescribing, encouraged by overinterpreted observational studies and curbed only by the first placebo-controlled randomised trial of hormonal replacement therapy. Lest we sleepwalk down that same path, let us hope that it will not take decades before the “andropause hypothesis” undergoes rigorous testing. The second NEJM article reports the early termination of a randomised, placebo-controlled clinical trial for excess adverse cardiovascular effects associated with testosterone supplementation.2 The study evaluated the somatic benefits of 6 months of daily use of testosterone gel in frail men over 65 years with low serum testosterone levels. As expected, this population had a high prevalence of cardiovascular disease, which would explain their low serum testosterone levels as a non-specific effect of chronic illness. The progressive excess of adverse cardiovascular effects in testosterone-treated men (23 men receiving testosterone v 5 receiving placebo in the trial’s total of 209 men) was unexpected but persisted despite the use of various definitions of adverse cardiovascular events (the original definition was broad and included unexplained syncope and peripheral oedema). As the study design was conventional in regard to testosterone dosage, titration and monitoring, these findings show a low cardiovascular safety margin for testosterone supplementation in frail older men. They differ from the findings of previous comparable placebo-controlled studies of testosterone use in older men, which reported no excess cardiovascular events,9 even in 12-month studies of men with cardiac failure.10 Nevertheless, these adverse findings cannot be considered surprising given the earlier onset and greater severity of cardiovascular disease in men, together with the refutation of the long-dominant hypothesis that oestrogen provides women with a degree of cardiovascular protection.11 As this second article2 highlights, the effects of a treatment that excessively increases risk for the most common cause of death — cardiovascular disease — overwhelm even substantial improvements in less common or non-fatal disorders. Hence, the study’s finding of a benefit (improved limb muscular strength) was overshadowed by adverse cardiovascular profiles, as has happened with other treatments, such as the WHI’s reductions in bone fractures and colorectal cancer, and the highly effective, gastric-sparing cyclooxygenase-2 (COX-2) inhibiting analgesics and the oral antidiabetic glitazones. A corollary is that overinterpreting the regular association of low serum testosterone in men with cardiovascular disease as a risk factor that might be ameliorated — rather than as a consequence — led to a misplaced focus on prostate cancer as the major risk of testosterone treatment in older men. Taken together, these two studies can be construed as pressing the accelerator and the brakes at the same time on testosterone prescribing for older men . . . with probably the usual effect of spinning wheels. However, several reflections arise for Australian clinical practice. First, Australia’s national guidelines for testosterone use,12 developed in 2000 and adopted by the Pharmaceutical Benefits Scheme as the criteria for subsidised testosterone prescriptions, are vindicated. They aim to restrict testosterone prescribing for age-related androgen deficiency without hindering it for pathologically based androgen deficiency. European and US guidelines (produced in 2005 and 2006, respectively) were republished recently, essentially unchanged.13,14 The northern hemisphere guidelines, in contrast to Australia’s, blur the distinction between pathologically based and age-related androgen deficiency, loosen the diagnostic criteria and lack regulatory force. Thus they minimise the diagnostic hurdle, leading to the perverse outcome of potentially encouraging rather than deterring unproven overuse of testosterone. Second, the EMAS definition of “late-onset hypogonadism” is not suitable for implementation in practice. Findings of the MMAS confirm clinical experience and are reflected in all clinical guidelines:12-14 serial serum testosterone levels in older men are sufficiently variable7 to require the results of at least two blood samples taken weeks apart to establish a sustained low level of serum testosterone. Hence, a definition reliant on a sample of single testosterone measurements is likely to be highly error-prone, due to regression to the mean and other sources of variability. It also relies on testosterone measurements by mass spectrometry, a superior technology not yet available in Australian pathology laboratories despite recognised limitations of testosterone immunoassays.15 Similarly, the so-called “free” testosterone variable, also used in the study but not recommended, is calculated by an inaccurate formula unsuitable for individual diagnosis.16 Third, reflection on these two NEJM articles makes evident the need to reinforce bans on direct-to-public advertising of testosterone supplementation. This critical protection depends on industry self-regulation. Without this protection, an avalanche of misguided testosterone prescribing awaits us, analogous to the massive, unregulated marketing of non-proprietary impotence drugs advertised on billboards and in the media, apparently beyond regulatory reach. Finally, testosterone prescribing for older men is best restricted to clinical trials where ethical oversight ensures appropriate design and warnings to participants. Age alone may not prove a valid indication, but this should not limit essential further research within the framework of placebo-controlled clinical trials aiming to define the benefits and risks of testosterone use in patients with the comorbidities of ageing, such as obesity, diabetes, metabolic syndrome and other chronic conditions.

David J Handelsman MB BS, FRACP, PhD

Introducing an innovative, evidence-based resource for use in the emergency department In early 2008, the National Institute of Clinical Studies (NICS) Stroke Clinical Reference Group was formed to develop an acute stroke care resource for use in emergency departments (EDs) in Australian hospitals. The NICS reference group used a care bundle approach to develop a guideline implementation tool based on specific recommendations from the 2007 National Stroke Foundation (NSF) Clinical guidelines for acute stroke management relevant for ED care.1 Although these guidelines were already available, there are well known barriers to guideline implementation in the ED. These include increasing demand and acuity, and the broad diversity of clinical presentations. Clinical information provided for ED clinicians needs to be concise and relevant to the emergency care context. The nine-member NICS reference group represented a collaboration between stroke and ED specialists, prehospital providers and managers of state-based stroke networks, with additional guidance from the NSF. Over the following 12 months, a consultative process took place, with a combination of face-to-face and teleconference meetings and email exchanges. The reference group used a Delphi process to reach consensus. In December 2009, the NICS released two documents — the Emergency department stroke and TIA care bundle: information and implementation package and the accompanying Summary for clinicians. These are available on the National Health and Medical Research Council (NHMRC) website (http://www.nhmrc.gov.au/nics/programs/emergency/stroke_tia.htm). This editorial presents a précis of the care bundle. Care bundles have already been shown to improve guideline compliance and lead to improved patient outcomes in several settings, including the ED.2-6 A care bundle is made up of a small number of best-practice recommendation components, is not as comprehensive as a guideline, and aims to identify critical recommendations relating to areas in which there is a significant practice gap or to act as a trigger to other best practice.7 The NICS care bundle needed to bring together several components to help clinicians provide quality care to adult patients who present to the ED with suspected stroke or transient ischaemic attack (TIA) by reducing morbidity and mortality and optimising patient outcomes (Box 1). The criteria for a component’s inclusion in the care bundle were determined by the model developed by the Institute for Healthcare Improvement in the United States:7 each component must be based on sound evidence; the delivery of each component must need improvement; the delivery of each component must be achievable in terms of universally available resources; no component should be a major source of controversy; and the delivery of each component must be measurable. Two components — stroke unit care and thrombolysis — are not included in the care bundle. We acknowledge the importance of stroke unit care — and thrombolysis for patients who meet the criteria for its use — when appropriate resources are available. The NSF recommendations, along with similar international guidelines, state that thrombolysis should only be given under the authority of a specialist team with expert knowledge of stroke management and with pathways and protocols in place to guide the acute phase.1,8-10 Although there is level I evidence that thrombolysis and stroke unit care are effective early interventions for stroke,2 currently thrombolysis is only offered in 28% of acute hospitals that manage stroke patients, and stroke unit care is only available in a third of hospitals across Australia.8 The reference group considered all of these factors and decided, by consensus, not to include thrombolysis and stroke unit care in the care bundle, as the necessary resources to support these are not universally available. However, the reference group believes that an emphasis on the first component of the bundle — a rapid initial stroke screen — could lead to earlier referral to stroke specialists and rapid access to computed tomography or magnetic resonance imaging to confirm the diagnosis and develop a management plan that would consider thrombolysis if clinically appropriate.11 This illustrates how the components of the care bundle may trigger additional best-practice recommendations as a natural consequence and establish joint clinical decision making with other disciplines to improve patient care (Box 2). The NICS clinical reference group is planning to collaborate with key stakeholders in 2010 to evaluate the effectiveness of the care bundle, both as a format for providing specific guideline recommendations to a target audience and in terms of the impact on stroke care in the ED. An implementation plan and auditing tool have also been developed to assist in the uptake of the recommendations. The NICS care bundle is based on the 2007 NSF clinical guidelines,1 and its recommendations are consistent with the current draft of the 2010 NSF guidelines. It is intended that the care bundle will evolve to ensure that recommendations relevant to the ED remain current. 1 Components of the NICS care bundle Rapid initial stroke screen (grade C; level II)* ABCD2 assessment† for suspected TIA (grade B; level II) Urgent‡ CT or MRI (grade A; level I) Nil by mouth until bedside swallow screen (within 24 hours) for stroke (grade C; level I) Aspirin as soon as possible,§ if haemorrhage excluded (grade A; level I): 150–300 mg one-time loading unless contraindicated Physiological monitoring and treatment Neurological status (grade C; levels II and III-2): regular monitoring to establish baseline and identify change Blood glucose (grade B; level II): cautious treatment of markedly elevated blood glucose levels; early, intensive maintenance of euglycaemia is not recommended. Avoid hypoglycaemia Blood pressure (consensus¶): cautious lowering by no more than 10%–20% if extremely high (≥ 220/120 mmHg); monitor for neurological deterioration Hydration status (grade B; level II): maintain euvolemia NICS = National Institute of Clinical Studies. TIA = transient ischaemic attack. CT = computed tomography. MRI = magnetic resonance imaging. * Evidence-based grades and levels as per 2007 National Stroke Foundation clinical guidelines.1 † A seven-point score calculated from age, blood pressure, clinical features, duration of symptoms, and diabetes status. ‡ “Urgent” means as soon as possible, but certainly within 24 hours.1 § “As soon as possible” means within 48 hours.1 ¶ Recommended best practice based on clinical experience and expert opinion. 2 Application of the NICS care bundle* Case study 1: a 68-year-old man presents to a hospital emergency department (ED), having woken with marked weakness of his left arm. Enquiry establishes that he was fine when he went to bed 7 hours earlier. The patient’s blood pressure (BP) at triage is 186/99 mmHg. The triage nurse is concerned that the patient is having a stroke. Case study 2: a 74-year-old woman with a history of type 2 diabetes mellitus and hypertension presents to a metropolitan tertiary hospital ED. She is unable to speak and has no strength in her right arm or right leg. Her friend states that the symptoms started only 2 hours ago. The patient’s BP is 170/95 mmHg; her heart rate is 80 beats/min and the heart is in sinus rhythm; and her blood glucose level is 9 mmol/L. The following care is provided for these patients, consistent with the use of the care bundle: as part of the patient’s assessment, and based on clinical findings, conduct a rapid initial stroke screen using a validated stroke screening tool to determine whether the patient is likely to have had a stroke. If a stroke is suspected, promptly refer the patient for expert stroke management — this may include referral to a stroke unit, or thrombolytic treatment (which is likely for the patient in case study 2); order an urgent computed tomography (CT) scan of the brain; ensure no oral intake until the patient undergoes a swallow screen for dysphagia; maintain hydration via intravenous or nasogastric fluids; administer aspirin (150 mg) within 48 hours if the brain CT scan excludes haemorrhage (if the patient in case study 2 proceeds to thrombolysis, delay aspirin treatment until 24 hours after thrombolysis); monitor the patient’s neurological status, blood glucose level, BP and hydration status to prevent further deterioration. NICS = National Institute of Clinical Studies. * The NICS care bundle was written for the care of stroke patients while in the ED. If the patient is transferred out of the ED early in his or her care, it is anticipated that the remaining components of the bundle will still be provided in the new setting.

Jayantha I Weeraratne MB BS, FACEM · Annette J Lenstra BSc, GradDip(Gov) · Andrew W Lee MB BS, MPH, FRACP · Kelvin M Hill BAppSci(Physio), GradDip(BusComm) · Susan D Huckson BAppSci, RN, ICU(Cert) · Jodie L Clydesdale BNurs, GradDip(ClinNurs)

Objective assessment of the health of the population is the key to policy and planning Accurate, timely information about a population’s health, health risks and use of health services and medicines is essential for planning and evaluating health policies and care. Health surveys based on representative probability samples of the population are designed to provide this by collecting data on health behaviours, health determinants such as socioeconomic disadvantage and obesity, prevalence of diseases, need for health care and whether this has been provided, functional capacity, and nutritional status.1 Such surveys can be classified as health interview surveys or health measurement surveys. The former are based on interviews or self-administered questionnaires and rely on a participant’s subjective assessment, while the latter include the addition of anthropometric, physiological and clinical measurements and tests (such as lung volume spirometry) and/or the collection of blood and other biological samples.2 Thus, the health measurement survey generally provides more objective data than the health interview survey; for example, on the prevalence of various diseases and risk factors, where self-reported information is known to be quite inaccurate (sometimes due to the fact that the disease has not yet been diagnosed).1 The recent announcement of a national Australian population health survey program using objective measures3 is therefore a welcome initiative for the community, health practitioners and policymakers alike. National health measurement survey programs have been conducted regularly in other countries for many years. The longest such series is in the United States, where the first national survey was carried out in 1959 — now known as the National Health and Nutrition Examination Survey (NHANES), it celebrated its 50th anniversary in 2009.4-6 European examples include the Finnish surveys from the 1970s, German and Norwegian surveys from the 1980s, and English and Scottish surveys from the 1990s.1 These survey programs have provided their countries with rich and unique national data sources for monitoring important health issues and formulating public health policies. In the US, for example, federal agencies and other public health organisations use data from NHANES to assess nutritional status and its relationship to health promotion and disease prevention.4,5 Survey findings also serve as the basis for national standard physical measurements like height, weight and blood pressure. Health science researchers use information from the survey to develop public health policy, programs and services, and expand the health knowledge of the nation.4 As a result, numerous advances in public health and nutrition have directly benefited US citizens’ health from the use of survey data to: document blood lead levels before and after the removal of lead from gasoline, paint and other household agents; quantify second-hand smoke exposure and evaluate the impact of policies to reduce or eliminate this exposure; identify low levels of folate in the population and the subsequent increase in these levels after folic acid fortification of foods; document the increase in obesity and diabetes in the population, including undiagnosed diabetes; and underpin the 1977 and 2000 paediatric growth charts.6 In Australia, there has been investment in collecting health information and concomitant biomedical and other measures in the past, but those studies, conducted through the 1980s and up to the mid 1990s, are no longer current, leaving significant gaps in our knowledge of the health of the population.7 More recent health measurement survey proposals have not proceeded, or have failed to deliver reliable national disease and risk factor prevalence estimates because of problems with study design, sampling and response rates.7-9 Now, the Australian Bureau of Statistics (ABS) is including a health measurement survey as an ongoing element of its Australian Health Survey program.3 This is certainly good news for health researchers, community planners, health practitioners and policymakers, and for the Australian public as a whole. The new survey program offers opportunities to provide an improved information base for national health policy development, health program planning and health research in ways that have not previously been possible. The Australian Health Survey program will have four components: National Health Survey, an existing household interview survey; National Aboriginal and Torres Strait Islander Health Survey, an existing household interview survey; National Nutrition and Physical Activity Survey, a new household interview survey; and National Health Measures Survey, a new health measurement survey.10 Planning is being undertaken by the Australian Government Department of Health and Ageing, in partnership with the ABS and the National Heart Foundation of Australia. Beginning in 2011, a representative sample of 50 000 Australians will be asked to complete the Australian Health Survey, representing “the most comprehensive health survey ever undertaken by the ABS”.3 Participants will also be asked to provide voluntary blood and urine samples to allow testing for nutritional status and early indicators of disease, such as high blood cholesterol or glucose levels.10 The investment in this national health survey program, with its inclusion of objective measures, will provide a firm foundation for health policy development in the 21st century, with undeniable benefits for individuals and the Australian community as a whole.

Diana M S Hetzel MB BS · John D Glover BEc, BA

The epidemiology of influenza pandemics demands that Aboriginal and Torres Strait Islander people occupy centrestage in future planning The first wave of pandemic (H1N1) 2009 influenza (pH1N1) broke more heavily on Australia’s Aboriginal and Torres Strait Islander populations than on non-Indigenous Australians. The burden of disease in Aboriginal and Torres Strait Islander people was highlighted by the first Australian death associated with pH1N1 infection: a young Aboriginal man from a remote area of Western Australia who died on 19 June 2009 in an Adelaide hospital.1 The differences between the populations are stark, with Aboriginal and Torres Strait Islander people indisputably over-represented in severe pH1N1 disease. In the Top End of the Northern Territory, pH1N1 rates of notification, hospital admission and intensive care unit (ICU) admission were higher for Aboriginal and Torres Strait Islander people than for the non-Indigenous population (3.5 times, 12 times and 5 times, respectively).2 Similar profound differences have been recorded for Aboriginal communities in New South Wales: Aboriginal people hospitalised with pH1N1 were younger than their non-Aboriginal counterparts (median age of 24.5 years compared with 31.7 years), and the age-standardised rate ratios for Aboriginal to non-Aboriginal admissions to hospital, admissions to ICU and death during the 2009 pandemic wave were 3.2, 4.0 and 4.5, respectively.3 Overall, from May to October 2009 in Australia, Aboriginal and Torres Strait Islander Australians, who comprise 2.5% of the population, accounted for 16.0% of hospitalisations with pH1N1 and 9.7% of pH1N1 admissions to an ICU.4 A fivefold increase in risk of death due to pH1N1 was also reported.5 This experience demands a greater focus on the needs of Aboriginal and Torres Strait Islander communities and their prioritisation in future pandemic planning. We should not have been surprised, as history tragically demonstrates disproportionate morbidity and mortality for Aboriginal and Torres Strait Islander people in previous pandemics.6 It is thus exceedingly disappointing to discover no mention of Aboriginal and Torres Strait Islander Australians in the revised National Action Plan for Human Influenza Pandemic (NAP).7 The 2010 NAP fails to identify Aboriginal and Torres Strait Islander people as a high-risk group during the H1N1 2009 pandemic, although it acknowledges other risk groups that have been recognised internationally and in Australia: severe cases occurred in people with underlying chronic conditions such as respiratory diseases, cardiovascular disease, diabetes, autoimmune disorders and obesity. Pregnant women were also at an increased risk of serious disease.7 It is inexplicable that while Aboriginal and Torres Strait Islander people were identified as a priority group for the rollout of the pH1N1 influenza vaccination — a commendable and necessary preventive strategy — they are overlooked in the NAP.8 Although the Australian Health Management Plan for Pandemic Influenza9 states an equity commitment, and a subsequent appendix10 produced during the “Protect” phase of the 2009 pandemic endorsed the need for partnership between all health care providers in case and contact management among the Aboriginal and Torres Strait Islander population, respectful partnership between governments and Aboriginal and Torres Strait Islander communities to identify culturally appropriate and effective prevention and mitigation strategies enjoys no mention. Given that the NAP is the peak plan for guiding preparations for future pandemics, there is a fundamental need for governments to acknowledge and respond effectively to the specific requirements of Aboriginal and Torres Strait Islander people. Prevention and preparedness must include government support of planning in respectful partnership with Aboriginal and Torres Strait Islander communities, health organisations and representative bodies. Mandating this support and partnership at all levels of government will allow a greater understanding of infection risk and identification of cultural, social, economic and health service factors that may contribute to poor health outcomes, and ensure culturally safe and effective prevention and mitigation strategies. A national project, funded by the National Health and Medical Research Council, working with Aboriginal and Torres Strait Islander communities and health services in NSW, Queensland and Western Australia is learning about feasible and culturally appropriate containment strategies.11 A strong theme emerging from this work is the message to government: “Ask us, listen to us, share with us”. The ability of Aboriginal and Torres Strait Islander communities to develop novel practical mitigation measures has been a particular feature of this respectful engagement that has already informed government strategies in NSW.3 The epidemiology of the current and previous influenza pandemics demands that Aboriginal and Torres Strait Islander people occupy centrestage in future planning. Solutions to limit the burden on Aboriginal and Torres Strait Islander populations exist, but respectful partnership is necessary to unearth them. The partnership must not be a token one, but one developed through engagement with communities, and with the flexibility to be localised to meet the specific needs of diverse urban, rural and remote Aboriginal and Torres Strait Islander communities in all states and territories. Health information delivered with a local flavour is a key message from the project. “Ask us, listen to us, share with us” is a strong message that governments must heed if the impact of pandemic influenza on Aboriginal and Torres Strait Islander communities is to be limited.

on behalf of the Aboriginal and Torres Strait Islander Community Influenza Study Group

Circumcision now to prevent heterosexual HIV transmission in 2030 makes sense Australia is rightly proud of its response to HIV. Thanks to superb formulation of public policy in the early days of the epidemic, it is not only a low-prevalence country but an international leader in many aspects of its clinical and public health responses. To maintain this fine record, Australia should change policy so that infant male circumcision rates are boosted in the face of rising heterosexual transmission of HIV. Regular surveillance indicates that HIV in Australia is slowly following the trend in Western Europe and North America toward an increased proportion of transmission occurring through heterosexual contact.1 Although the epidemic in Australia is likely to remain concentrated for some time among men who have sex with men, the proportion of new diagnoses attributable to heterosexual contact has risen from the negligible levels of the epidemic’s early days.1 The World Health Organization, the Joint United Nations Programme on HIV/AIDS and the Global Fund to Fight AIDS, Tuberculosis and Malaria have endorsed male circumcision to control HIV attributed to heterosexual contact in hyperendemic areas, stating: “The efficacy of male circumcision in reducing female to male transmission of HIV has been proven beyond reasonable doubt. This is an important landmark in the history of HIV prevention.”2 This raises the question of whether low-prevalence countries such as Australia — with an increasing proportion of HIV cases attributed to heterosexual contact — should consider increasing the rate of infant male circumcision to reduce future HIV infections. The protection conferred to heterosexual males by circumcision is similar in hyperendemic and low-prevalence settings.3-5 In 2008, the Centers for Disease Control and Prevention (CDC) concluded that male circumcision “may also have a role in the prevention of HIV transmission in the United States”.3 The CDC is now formulating a new policy.4 Being a low-prevalence country does not preclude a population-wide approach to HIV prevention. For example, we test pregnant women to prevent cases of vertical HIV transmission. Infant male circumcision would be a comparable, albeit more interventionist, population-wide strategy. A wealth of research has shown that the foreskin is the entry point that allows HIV to infect men during intercourse with an infected female partner.5,6 Soon after the HIV pandemic was first recognised, much lower HIV prevalence was found in areas of sub-Saharan Africa where more than 80% of males had been circumcised than in areas where the circumcision rate was less than 20%.5,6 These findings were then replicated in Asia.7 In Australia, infant male circumcision was once routine, but plummeted in the 1970s. Circumcision of males is now referred to by many as a “surgical vaccine” against a wide variety of infections and adverse medical conditions over the lifetime.5,6,8,9 The public health benefits include protection not just from sexually transmitted HIV, but also from some common sexually transmitted infections and other conditions.4-6 Although it can be performed at any age, the ideal time is infancy, when adverse effects are uncommon.4-6 Considerable evidence, including data from randomised controlled trials, shows that male circumcision has no adverse effects on sexual function, sensitivity or satisfaction.4-6,8 At present, the major obstacle to increasing the rates of infant male circumcision in Australia is an influential Royal Australasian College of Physicians policy, which has been criticised on scientific grounds.10 A draft of a new policy has also been criticised in a detailed petition by 38 academic and clinical experts (including Fellows of the College). Another barrier is the Medicare rebate, which has been reduced steadily in real terms over many years. No state or territory Department of Health except Queensland Health allows elective infant male circumcision to be performed in public hospitals. Despite official discouragement, Medicare statistics show a rise in the rate of infant male circumcision in Australia from 13% in 1998 to 19% in 2009. Boosting the rate in Australia, as a long-term strategy to reduce HIV transmission (in combination with other interventions), is sound public health policy. Male circumcision is one of the most powerful interventions that is currently available in the fight against HIV.8,9 The prospect of the availability of a vaccine over the next 20 years is unlikely. Thus, circumcision now to prevent heterosexual HIV transmission in 2030 makes sense. In addition to preventing HIV transmission, other benefits, high cost-effectiveness11 and risk–benefit balance5,10,11 justify acceptance of male circumcision as a sensible public health measure.3,5,6 It should be viewed as part of a safer sex package. Condom use remains essential, with promotion of condom use plus circumcision of males being analogous to seatbelts plus airbags for reducing the road toll. Australia would also be acting compassionately if it promoted infant male circumcision in the Asia–Pacific region, especially in Papua New Guinea where a generalised HIV epidemic has become well established. A commitment to increasing infant male circumcision should complement earlier commitments to other strategies for prevention of sexually transmitted infections, including condom use. Twenty-nine years after the existence of this epidemic was first announced, it is clear that a new chapter has opened with the recognition that male circumcision substantially reduces female-to-male HIV transmission. Australia would be wise to take advantage of this knowledge.

David A Cooper MD, DSc · Alex D Wodak AM, FRACP, FAChAM, FAFPHM · Brian J Morris PhD, DSc, FAHA

We need those not directly in the firing line to appreciate the evidence on overcrowding Resolving access block and emergency department (ED) overcrowding is finally front and centre of the political agenda. Governments have heeded calls for action and responded by announcing a national access target to improve timely treatment in Australian EDs. After the target is implemented, “anyone presenting to a public hospital emergency department will be admitted, referred for treatment or discharged within four hours of presentation, where it is clinically appropriate to do so”.1 In the United Kingdom, a similar 4-hour target has been in place since 2004, and, despite a recent policy announcement concerning its abolition from April 2011, timeliness of care and avoidance of delay once a patient is ready to move to a ward “will always remain an important element of any balanced approach to quality”.2 Reducing the number of hospital beds and increasing occupancy above 85% in the name of operational efficiency have clearly had a negative effect, as the demand for hospital beds in Australia exceeds supply.3 The root cause of the problem will remain unless hospital capacity is addressed in an integrated approach at both national and state levels.3 In this issue of the Journal, several articles discuss hospital occupancy. Keegan articulates the evidence for using hospital bed occupancy as an operational quality measure and target.4 As hospital bed occupancy rises above 85%, adverse effects include increased rates of hospital-acquired infections, staff health deterioration and escalating hospital inefficiency. Keegan advocates a shift to using patient outcome measures, rather than current process measures to judge health system function. This evidence presents a counterpoint to a discussion started by Bain and colleagues earlier in the year, which suggested that the 85% target occupancy figure is “a candidate for myth status” and is “both simplistic and likely to lead to flawed policy”.5 Jones points out that occupancy and hospital size are linked, and therefore broadens the debate to include hospital size.6 He explains clearly what we all know intuitively: hospital planners have been delivering hospitals that are too small. When planning new hospitals, future bed requirements would be more realistically estimated by using readily available figures for occupied bed-days and examining trends over time, compared with just using admission numbers and length of stay. This would take into account factors influencing volatility of demand for beds. Trends in occupied bed-days show that English hospitals needed as many beds in 2007 as in 1998, despite a large reduction in available beds. The situation is the same in Australia and Canada, yet there is a pervading belief among planners that increasing efficiencies will account for any shortfalls. Jones discusses factors apart from demography that affect demand, including clinical practice changes, environmental cycles, and the increasing need for end-of-life care. He concludes, “can we please have a true evidence-based debate . . .?”, as patients and clinical staff deserve to benefit from the tools required to deliver effective and efficient health care. It is very pleasing to see the debate continue; the rapid growth in the published literature on access block and ED overcrowding since 2007 demonstrates increased focus on this issue.3 But further than this, we need those not directly in the firing line to appreciate the evidence on access block and ED and hospital overcrowding, so that we see the end of policy setting without attention to relevant system capacity issues. For instance, the Australian Commission on Safety and Quality in Health Care has identified reduction of hospital-acquired infection as a priority;7 however, interventions are focused only at the individual staff and patient level, without mention of the system issue of overcrowding. Similarly, while EDs are the most commonly complained about sites of care in New South Wales, and a third of these complaints relate to access to care,8 the NSW public health system’s incident management system does not include access block and ED overcrowding as reportable incidents. Failure to acknowledge the causes and consequences of high hospital bed occupancy is seen in well publicised health system responses to incidents that have occurred in overcrowded EDs. The solutions proposed in response to these incidents so far have not included fixing the underlying reason for the patient being stuck in the waiting room — lack of hospital capacity.9,10 Transparent performance reporting and new national standards are part of planned health reforms in Australia, but there are problems with the accuracy of current performance data,11 and, as Keegan points out, development of meaningful outcome measures of patient care is required.4 In the meantime, the verdict is in on access block, high bed occupancy and ED overcrowding — they are bad for patients, staff and the system itself. It is time hospital capacity was also on the patient-safety policy agenda.

Sally M McCarthy MB BS, MBA, FACEM

The importance to patient safety of clinician-led mortality auditing needs system-wide recognition In April 2010, the Council of Australian Governments (COAG) agreed on health and hospitals reform, with the establishment of the National Health and Hospitals Network. The aims of the network include “helping patients receive more seamless care across sectors of the health system” and “improving the quality of care” with “high-performance standards”.1 As a key component of the reforms and a funding condition, health facilities will be required to regularly report performance data to the federal government. Data will be based on national performance indicators that are already agreed to by COAG and address “access to services, quality of service delivery, financial responsibility, patient outcomes and/or patient experience”.2 Disappointingly, the COAG reforms appear to neglect clinical patient outcome data that are reported for the purpose of monitoring and improving patient safety, not least of which are mortality data. In Australia, pooled data on anaesthesia-related and surgery-related perioperative mortality are routinely analysed by the Australian and New Zealand College of Anaesthetists Mortality Working Group and the Royal Australasian College of Surgeons’ Australia and New Zealand Audit of Surgical Mortality, respectively.3 The practice of anaesthesia is highly regarded for its patient-safety record, and mortality reporting is considered an important tool in monitoring safety by informing standards of care with respect to equipment, techniques and classification of patients’ fitness.4 This year will see the first national public reports on surgical mortality in Australia, with early reports from Western Australia supporting the argument that clinician participation and leadership in mortality audits produce changes and improvements in patient care. Data from WA show that the proportion of deaths associated with deficiencies of care has fallen, and 73% of participating surgeons have changed their practice in at least one way.5 Clinician-led mortality reporting can contribute meaningfully to health reform but, sadly, there are few other instances of peer review of treatment-associated mortality and centralised public reporting in Australian health systems. Closer examination reveals that even the national anaesthesia dataset is incomplete because several states do not participate in mortality audits.3 Cooper and Gaba, in an appraisal of international anaesthesia-related mortality reporting, explain the limitations of, and possible reluctance to participate in, mortality reporting, which they claim is “plagued by confounding variation in definitions, relatively small sample sizes from selected institutions, and the lack of large population studies”.4 The Special Committee Investigating Deaths Under Anaesthesia (SCIDUA) in New South Wales — the longest-serving committee of its sort in Australia — is an excellent model of clinician-led mortality reporting.6 Appointed by the NSW Minister for Health and administered by the Clinical Excellence Commission (CEC), SCIDUA reviews all deaths occurring within 24 hours of anaesthesia or sedation. Data analyses by SCIDUA, which this year is celebrating its 50th anniversary, have substantially contributed to mortality reporting internationally.3,7,8 The Australia and New Zealand Audit of Surgical Mortality developed from the SCIDUA model via the NSW Special Committee Investigating Deaths Associated With Surgery (established in 1993, the latter is now the Collaborating Hospitals Audit of Surgical Mortality, and it too is administered by the CEC). SCIDUA’s terms of reference provide solutions to several of the limitations described by Cooper and Gaba4 and are useful starting points for other groups establishing mortality registers.6 Important starting points include a clearly defined preoperative period and phrasing of degrees of contribution to death. SCIDUA’s registry includes both expected and unexpected deaths, enabling identification of unanticipated emerging threats to safety, such as those associated with new drugs and procedures. Patients are classified according to their risk of death from comorbidities. This classification allows data about expected and unexpected deaths to be analysed separately, an essential requirement for trend analysis when concomitant increases in patient and surgical complexity could confound mortality rates. All sources of data obtained by SCIDUA are protected by qualified privilege under section 23 of the Health Administration Act 1982 (NSW). Of historical interest, SCIDUA was responsible for this section of the Act, which ensures qualified privilege to peer-review committees across all clinical disciplines within NSW. Recent changes to the NSW Public Health Act 1991 and Public Health (General) Regulation 2002 have led to a modified procedure for reporting deaths occurring within 24 hours of anaesthesia or sedation (now classified as a Category 1 scheduled medical condition). However, the new procedure retains not only mandatory notification of perioperative death but protection by privilege of anaesthetists who voluntarily submit information and analyses. These provisions encourage frank and comprehensive reporting, evidenced by the breadth of information available for analysis.3 Lessons in maintaining patient safety generated through SCIDUA are communicated widely. SCIDUA sends a confidential report outlining its conclusions about the circumstances contributing to death to the notifying anaesthetist. Pooled de-identified data are incorporated into the Australian and New Zealand College of Anaesthetists’ national triennial mortality report.3 The health care community is alerted to perceived safety risks through an annual report provided to the NSW Minister for Health and through periodic reports published in national and international journals.9,10 All deaths in all health facilities should be subject to clinical scrutiny. De-identified and pooled data should be systematically analysed for the purpose of continually monitoring patient safety as therapies change. The models provided by SCIDUA and, more recently, the Australia and New Zealand Audit of Surgical Mortality are there to be applied by all health care providers. Food for thought!

Leonie M Watterson MB BS, FANZCA, MClinED · Ross B Holland MB BS, FANZCA, FHKCA · Jan M Davies MSc, MD, FRCPC · Clifford F Hughes AO, MB BS, FRACS

Recent reviews suggest a low risk of allergic reactions to egg-cultured influenza virus vaccines Australian influenza notification and hospitalisation rates are highest in children aged under 5 years,1 the group most commonly affected by egg allergy. While vaccines derived from influenza virus grown in mammalian cell cultures exist, those currently distributed in Australia and New Zealand are grown in hen eggs. The ability to safely vaccinate egg-allergic individuals (particularly in the context of epidemic influenza) will remain an important public health issue, well after concerns surrounding recent non-allergic adverse reactions in young children subside (Australian governments recently suspended seasonal flu vaccination for healthy children aged under 5 years; see http://www.immunise.health.gov.au). Product information and current Australian vaccination guidelines list egg anaphylaxis as an absolute contraindication to influenza vaccination,2 yet recent studies suggest that most egg-allergic individuals can be safely vaccinated. Most reported cases of anaphylaxis in egg-allergic patients after influenza vaccination occurred over 20 years ago, when the amount of egg protein in vaccines was substantially higher. The amount of egg protein (measured as ovalbumin) in vaccines distributed in Australia and New Zealand in recent years has been about 1 μg or less per dose (manufacturer data), which is substantially less than the estimated 130 μg likely to trigger reactions in patients with egg allergy if taken orally.3 Are concerns about vaccinating egg-allergic individuals evidence-based? Recent reviews suggest a very low risk of allergic reactions to influenza vaccination.4 A United States population study reported 11 cases of non-fatal anaphylaxis (none involving egg allergy) after 48 million doses of influenza vaccine had been given.5 Although this suggests there is a low risk of harm from the vaccine, patients with egg allergy were probably excluded from the vaccination program. More useful information is obtained from recent prospective studies. In a US study of 83 egg-allergic patients (27 with anaphylaxis) and 124 controls, positive vaccine skin tests were detected in four allergic patients and one control subject, yet all tolerated split-dose vaccination (a 10% dose followed by the remaining 90% 30 minutes later).6 An Italian study demonstrated a similar safety profile in 44 children with asthma and egg allergy (10 with anaphylaxis).7 In a Canadian study of split-dose H1N1 vaccination of 830 egg-allergic children, nine developed rash (treated with antihistamines) and three developed bronchospasm, but none progressed to anaphylaxis.8 In an expanded vaccination program, the same study reported rash, cough, or throat irritation or constriction in 71 of 3640 patients, but none developed anaphylaxis.8 In Western Australia, after the death from influenza of three otherwise healthy preschoolers in 2007, 165 egg-allergic children aged 6 months to 16 years (48 with anaphylaxis) were vaccinated. One patient developed mild facial urticaria after the first dose, but tolerated the second dose.9 In a recent US study, 164 of 171 patients (aged 6 months to 18 years) with non-anaphylactic egg allergy tolerated split-dose vaccination. Six experienced urticaria or wheeze after the 10% vaccine dose and one experienced flushing and hives after the 90% dose, but none had anaphylaxis.10 British, Canadian, European and US consensus guidelines4,8,11,12 suggest that most patients with egg allergy can safely receive seasonal and H1N1 vaccines if they contain no more than 1 μg/dose of egg ovalbumin. The Australasian Society of Clinical Immunology and Allergy concurs with these views and has released guidelines for vaccination of the potentially egg-allergic patient (http://www.allergy.org.au/content/view/27/8). We acknowledge that these proposals are at variance with Australian immunisation guidelines.2 People presenting for vaccination may be classified into three risk groups: Those considered to be at no additional risk. This includes people with non-egg food allergy, past egg allergy (who can now eat whole egg), and family (not personal) history of egg allergy, as well as those who react to raw egg but can tolerate at least a teaspoon of lightly cooked egg (eg, scrambled or boiled). This group can receive the vaccine as a single dose, followed by the 15-minute observation period recommended in Australian guidelines2 (20 minutes in NZ). Importantly, egg allergy is not a contraindication for the measles–mumps–rubella vaccine, which contains no egg protein. Those with non-anaphylactic allergic reactions to eggs or egg-containing food. Some authorities recommend a 10%–90% split-dose regimen, 30 minutes apart, if no adverse reaction occurs after the first dose; others recommend a single dose. Data from split-dose protocols6-10 have not indicated any significant adverse reactions in this risk group, despite administration of the full dose over 30 minutes. Based on current evidence, we suggest that the vaccine can be safely administered as a single dose with a 30-minute observation period, rather than the standard 15 minutes. Those who have had egg anaphylaxis in the past, and those who have never ingested egg in any form, but have had positive skin or blood test results for egg allergy. As reactivity and severity cannot be assessed in advance, these patients merit consideration as a potentially higher-risk group. The decision to vaccinate should include a risk–benefit evaluation of the vaccination, consultation with an allergy specialist (including initial telephone contact), direct medical supervision of vaccination, and use of a split-dose protocol (10%–90%, 30 minutes apart), with another 30-minute observation period after the final dose. Skin-prick or intradermal allergy testing with the vaccine before administration is not recommended, as results correlate poorly with vaccine tolerance. If the first vaccination is tolerated, the second vaccine dose can be given as a single dose in the same year. Since tolerance one year does not guarantee safety the next (due to yearly fluctuations in egg vaccine content), we recommend that the same process be followed each year. Rare allergic reactions (including reactions to non-egg vaccine ingredients) cannot be totally excluded. Vaccines should always be administered in facilities with health professionals able to recognise and treat anaphylaxis. Adverse events following vaccination should be reported to the Advisory Committee on the Safety of Medicines (Australia) or Medsafe (NZ), documenting the timing of onset, nature and severity of symptoms, likelihood of a relationship with vaccination, and any other relevant health details.

Raymond J Mullins MB BS,PhD, FRACP · Andrew Kemp MB BS, PhD, FRACP · Michael Gold MB ChB, MD, FRACP

Identifying the emerging threats for which we must be vigilant In 1922, infectious diseases accounted for 15% of all deaths in Australia, but this rate declined dramatically to 1% by 2007 due to a combination of antibiotics, vaccination and public health measures. Yet infectious diseases continue to feature prominently in Australia. The Australian Institute of Health and Welfare has just released its biennial publication on the health of the nation, Australia’s health 2010 — a statistical and informed commentary that examines a variety of health issues dominating the national landscape.1 Here, I summarise the report’s chapter on infectious diseases to paint a picture of where we are today and the challenges we may well face in our future. Among vaccine-preventable diseases, invasive meningococcal disease remains one of the most feared. However, notification data continue to show a pleasing trend of decreasing cases annually.1 Much of this decline can presumably be attributed to the introduction of the meningococcal C conjugate vaccination program in 2003.2 Not surprisingly, cases of the B strain, for which there is no vaccine, dominate the notifications, although numbers have been stable and certainly haven’t increased. Similarly, rates of invasive pneumococcal disease remain steady and well below those seen before the introduction of universal infant vaccination in 2005.1 Concerns continue that there will be a surge of invasive pneumococcal disease due to non-vaccine serotypes — so-called serotype replacement — following introduction of the conjugate vaccination program that will offset any reductions from the program; however, this has not yet happened. Pertussis notifications reached unprecedented levels in 2008 and 2009, with a particularly large increase in the proportion of cases in 0–4-year-olds — the group most vulnerable to severe disease from pertussis.1 Yet it is likely that this increase in notifications can at least partly be explained by increased testing and easier access to better tests, such as polymerase chain reaction (PCR). The world experienced its first influenza pandemic in 41 years with the outbreak of pandemic (H1N1) 2009 influenza (popularly known as “swine flu”). There were over 45 000 laboratory-confirmed notifications of influenza in Australia in 2009, eclipsing those of previous years — by comparison, in 2007, the other severe influenza year in recent times, there were 10 445 notifications. However, there was undoubtedly more testing conducted in 2009. The figure shown in the Box elegantly demonstrates how the swine flu virus behaved like a typical pandemic strain, predominantly affecting adolescents and young adults, while the 2008 “standard” seasonal strain mainly targeted people at the extremes of age.1 Although pandemic influenza has had the highest profile in recent times, chlamydia, with over 62 000 notifications, was the most highly notified infection in Australia in 2009 and remains an important issue among the sexually active. However, as with pertussis and influenza, increased testing has almost certainly contributed to the large number of infections seen recently.1 From 2000 to 2009, there was a decline in rates of newly diagnosed hepatitis B and C infections. Particularly among adolescents and young adults, this decline may be due to factors such as a reduction in injecting drug use and a vaccination program for adolescents against hepatitis B infection. Despite this, however, chronic hepatitis B and C infections are looming as long-term challenges for Australia.1 One model predicts that the 2008 figure of 187 000 people living in Australia with chronic hepatitis B infection could markedly increase to 276 000 cases in 2017 if current practices and resources remain unchanged. This would be associated with a large increase in hepatitis B-related deaths, including those from hepatocellular cancer.3 It is estimated that 212 000 people were living with chronic hepatitis C infection in Australia in 2008, and these people are at risk of similar chronic sequelae as those with chronic hepatitis B infection.4 Challenges include increasing awareness of the diseases and improving access to treatment for affected people, many of whom are from marginalised groups (eg, non-English speaking migrants, Indigenous Australians and injecting drug users). The federal government has responded to these challenges by releasing its first national hepatitis B strategy and third national hepatitis C strategy.4,5 A dengue outbreak featured prominently in northern Queensland between November 2008 and June 2009. Around 1000 cases occurred during this 8-month period, matching the total for the preceding 9 years. The outbreak was characterised by all four strains of dengue circulating, including a virulent DENV-3 strain that had a shorter incubation period within both mosquitoes and humans.1 Hendra virus infection remains unique to Queensland, where outbreaks continue to occur, causing much angst among the public and communicable disease services alike. In 2008 and 2009, Hendra virus, which is transmitted to humans from infected horses, caused the deaths of two veterinary workers.1 There are two emerging infections of concern in Australia. First, hypervirulent Clostridium difficile (also known as PCR ribotype 027 or NAP1) infection has become well established in the health care systems of many northern hemisphere nations in recent years, with high case-fatality and bowel-resection rates. Although a milder form of the infection has been well established here for years, Australia had remained free of this particular hypervirulent strain until our first imported case was detected in Western Australia in 2009.6 This was followed in May 2010 by an outbreak among patients in a Melbourne hospital,7 raising concerns that it may become established in Victoria before spreading elsewhere. Second, the appearance of multiresistant gram-negative organisms such as Escherichia coli in returning travellers, especially those arriving from Asia, is of concern. Although colonisation with these organisms in the bowel is asymptomatic, the problem arises when they cause symptomatic illness, typically in the urinary tract. Few antibiotics are available to treat such infections, and they are often expensive (eg, carbapenems) or dangerous (eg, potential nephrotoxicity and ototoxicity from amikacin). One study found that, while 8% of travellers were colonised with multiresistant E. coli before leaving Australia, almost 50% were colonised on their return.1,8 (It appears that Customs officials may have to worry about more than concealed drugs in travellers’ bowels on their return to Australia!) The health inequities experienced by Australia’s Indigenous peoples are well recognised and apply to many infectious diseases. One example is acute rheumatic fever and rheumatic heart disease. Indigenous people in the Northern Territory have one of the highest rates in the world of these conditions and are around 20 times more likely to die from rheumatic heart disease than non-Indigenous Australians.9 Despite the advances in combating acute and chronic infectious diseases over the past century, both continue to present challenges to our health system, especially for certain Indigenous populations. Multiresistant gram-negative bacterial infections acquired from overseas and hypervirulent C. difficile infection are emerging threats in Australia for which we must be vigilant. This is in addition to infections caused by the already established multi-resistant nosocomial pathogens such as vancomycin-resistant enterococci. The need to isolate affected patients and use expensive antibiotics to treat them only further burdens the hospital system. A mandatory reporting system for certain hospital-acquired infections could be one way to address this. Although childhood immunisation programs have generally been successful, we need to be watchful for resurgent infections, such as pertussis, where immunity from childhood vaccination has waned. Finally, as last year’s swine flu outbreak demonstrated, a pandemic has the potential to consume considerable resources and generate widespread concern. While the 2009 influenza outbreak has passed, the potential for further pandemics and the need to prepare for them persist. Avian influenza, which continues to cause human infections overseas, immediately comes to mind in this regard. Age distribution of influenza notifications in a pandemic year (2009) versus a standard seasonal year (2008)* * Reproduced from Australia’s health 2010 with permission of the Australian Institute of Health and Welfare.1

Sanjaya N Senanayake FRACP, MAppEpid, MB BS

On 22 August 2010, the Australian Mitochondrial Disease Foundation will hold its annual Stay in Bed Day to raise awareness of a genetic disorder that robs thousands of Australians of their energy Mutations in mitochondrial DNA (mtDNA) were discovered to cause mitochondrial disease over 20 years ago.1 Initially thought to be a rare group of neurological disorders predominantly affecting children, it is now known that patients with mitochondrial disease can develop a broad range of symptoms (Box) and may present at any age from early in the neonatal period to very late in adulthood. Debilitating or fatal forms of mitochondrial disease are more frequent in children than in adults, but adult patients often have chronic multisystemic manifestations that require symptomatic treatment and regular long-term surveillance to minimise the chance of life-threatening episodes of acute illness. Mitochondrial disease may present a diagnostic challenge to the clinician. Clinical manifestations are variable (see Box), and family histories suggestive of an inherited condition may not be obvious due to the variability in phenotypic expression that characterises this group of disorders. Moreover, the lack of a “gold standard” test for its diagnosis and the fact that mtDNA analysis is not freely available to all Australians (only in Victoria) exacerbate the difficulties in diagnosing affected individuals. Why are mitochondrial disorders highly variable? This is due to a number of factors. First, there are hundreds of mtDNA mutations that cause a variety of different mitochondrial disease syndromes. Notably, most disease-causing mtDNA mutations are heteroplasmic. Heteroplasmy is the co-existence of both normal (wild-type) and abnormal (mutant) mtDNA within the same cell. Because there are multiple mitochondria within any given cell, the proportion of mutant mtDNA may vary between 0 and 100% within any given tissue. Thus, the tissue used for diagnosis becomes critical, with blood not being the most ideal tissue to sample.2 There is substantial evidence to indicate that the higher the heteroplasmic mtDNA mutational load within the tissue or cell, the greater the level of mitochondrial dysfunction.3,4 A minimum number of mutant genomes are required for the expression of disease, a phenomenon referred to as the threshold effect. The threshold effect is a relative concept, because the critical amount of mutation required to impair mitochondrial function will vary depending on the particular mtDNA mutation involved and the relative metabolic requirements of the tissue’s cells at any given time. Although there are occasional exceptions, higher proportions of mutant mtDNA have typically been observed in more severely affected patients.5 Finally, the proportion of mutant mtDNA may change rapidly between parent and daughter cell. This phenomenon, referred to as mitotic segregation, combined with the concept of heteroplasmy, at least partly explains why some family members may be more severely affected than others and how some patients manifest different clinical manifestations at different stages of their lives. Several studies have now found that pathogenic mtDNA mutations occur frequently in the general population. The first true population-based study showed that the most common pathogenic mutation, known as m.3243A→ G (typically associated with MELAS — mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes — syndrome), was found in one in 500 community-based Australians.6 All mutation carriers aged over 50 years had few or minor symptoms, but none had the clinical features of MELAS syndrome. Although age and other risk factors were not accounted for in the analysis, all m.3243A→ G mutation carriers had developed sensorineural hearing loss, a common but non-specific clinical symptom that frequently affects patients with mitochondrial disease. A second study in the United Kingdom confirmed this frequency of the m.3243A→ G mutation, reporting that it was found in one in 700 live births, although no clinical information on mutation carriers was given.7 The authors analysed a total of 10 common mitochondrial point mutations, and found a population prevalence of pathogenic mutation of more than one in 200 live births. Later, two studies investigating the population prevalence of a different point mutation, m.1555A→ G (originally associated with antibiotic-induced hearing loss), independently showed that this mutation was similarly found in one in 500 subjects.8,9 Children with this mtDNA mutation were asymptomatic, but older individuals were more likely to have developed associated symptoms. In addition to determining that mtDNA mutations were prevalent and usually unrecognised in the community,10 these findings raised questions about how and when mutation carriers become symptomatic during their lives. Should we consider mtDNA mutation carriers in the spectrum of mitochondrial disease? Given the lack of data about the factors that contribute to disease penetrance in mutation carriers, this approach could easily be justified. Patients who develop severe disease caused by their pathogenic mtDNA mutation could represent just the “tip of the iceberg”, with the vast majority of mutation carriers remaining only mildly affected. Changes in lifestyle and use of preventive strategies to delay the onset of symptoms (such as tailored exercise programs and avoidance of metabolic and physiological stressors) should be recommended to all mutation carriers in an attempt to reduce the individual’s risk of developing symptoms, although this may be ineffective in those who are destined to develop severe clinical manifestations. Longitudinal clinical studies of mutation carriers are warranted, to determine the natural history of mitochondrial disease and identify risk factors that contribute to developing severe or life-threatening disease versus mild or no symptoms during life. If the prevalence of mtDNA mutations in Australia is at least one in 250, then 90 000 Australians are potentially at risk of developing symptoms of a mitochondrial disorder. To raise community awareness of this genetic disorder, which robs thousands of Australians of their energy, the Australian Mitochondrial Disease Foundation will hold its annual Stay in Bed Day on 22 August 2010 (see http://www.amdf.org.au for details). Clinical manifestations of mitochondrial disease* Organ system Common clinical manifestations Adults Children Brain Stroke-like episodes, seizures, migraine-like headaches Epilepsy, stroke-like episodes Muscle Proximal myopathy Muscle weakness Ears Sensorineural hearing loss Sensorineural hearing loss Eyes Ptosis, external ophthalmoplegia, retinal pigmentary changes, optic atrophy Ptosis, external ophthalmoplegia, retinal pigmentary changes, optic atrophy Heart Cardiac arrhythmia, cardiomyopathy Cardiomyopathy, hypertrophic cardiomyopathy Endocrine Diabetes Diabetes Gastro−intestinal Intestinal pseudo-obstruction, constipation, abdominal bloating, dysphagia Vomiting, failure to thrive Respiratory Respiratory failure, recurrent aspiration, nocturnal hypoventilation Apnoea Renal Renal tubular acidosis Liver Liver failure * If a mitochondrial disease is suspected due to the presence of one or more of these clinical features, a muscle biopsy, genetic testing or referral to a specialised centre for assessment should be considered.

Carolyn M Sue MB BS, PhD, FRACP

Physicians need to be aware of this newly described complication Every year, thousands of Australians are prescribed bisphosphonates for the treatment of osteoporosis. They are highly effective agents, with numerous large clinical trials demonstrating a significant reduction in the risk of osteoporotic fractures as early as 6 months after commencement of therapy. Bisphosphonates such as risedronate, alendronate, etidronate, pamidronate and zoledronic acid have an excellent safety profile, although gastro-oesophageal irritation or transient flu-like symptoms may occur in patients receiving oral or intravenous bisphosphonates, respectively. Other side effects, such as renal impairment, uveitis and osteonecrosis of the jaw, have been described but are extremely rare. Since 2005, there have been several reports suggesting another potential side effect of long-term bisphosphonate therapy, namely the development of unusual fractures of the subtrochanteric or diaphyseal femur.1-4 Two initial case series described these femur fractures in a total of 12 patients (11 female) receiving current alendronate therapy. The mean age of these patients was 63 years and the mean treatment duration with alendronate was 6 years.2,4 The fracture pattern appeared morphologically distinct from the more common osteoporotic hip fracture and hence, in 2008, the term “atypical femur fracture” was introduced to describe a combination of three highly characteristic features: (i) a transverse or oblique fracture line occurring in (ii) an area of cortical thickening with (iii) a medial unicortical beak5 (Box). A further peculiar feature was the location of these atypical fractures in the subtrochanteric or mid-shaft femur, which is normally considered the strongest part of the femur. In 2007–2008, three retrospective analyses confirmed the predominance of this particular fracture pattern among bisphosphonate users.6-8 The largest of these included a study of 70 patients with non-hip femoral fractures, of whom 25 were receiving alendronate.6 The atypical fracture pattern was strongly associated with alendronate use, with a reported odds ratio of 139 (95% CI, 19–939; P < 0.001). The authors again noted that these fractures were associated with a longer duration of alendronate use (on average 4.4 years longer than patients without atypical fractures) and appeared to affect younger rather than older women. Most recently, a large 5-year retrospective study of non-hip femoral fractures found strong evidence supporting a potential association between oral bisphosphonate use and the occurrence of atypical fractures.9 Of 152 non-hip femoral fractures, 20 were classified as atypical following a detailed review of individual radiographs. Of the 20 patients, 17 had been receiving long-term therapy with either alendronate (n = 15) or risedronate (n = 2). According to this study, oral bisphosphonate use imparted a 37-fold increased risk of atypical versus typical osteoporotic fracture, with the atypical fracture pattern being 96% specific to oral bisphosphonate use.9 Other potential risk factors for developing atypical fractures include prolonged use of glucocorticoids,2,4,9,10 hormone replacement therapy,2 use of selective oestrogen receptor modulators,4 rheumatoid arthritis9,10 and vitamin D deficiency.9 The occurrence of groin or thigh pain, sometimes manifesting months before the acute fracture, has been described by several authors,1,4,7,8 with one group reporting its occurrence in 13 out of 17 (76%) atypical fracture cases.8 The pain is attributed to the development of unilateral stress fractures and should be viewed as an early warning sign in patients receiving bisphosphonate therapy. Several authors have also noted the occurrence of these fractures bilaterally.1-3,8-10 Attempts to elucidate the precise incidence of these fractures or to confirm their association with bisphosphonates on an epidemiological or observational scale have proved elusive. In 2009, a registry-based cross-sectional study of 11 944 patients failed to demonstrate a greater frequency of subtrochanteric or diaphyseal femoral fractures in patients receiving alendronate.11 Similarly, in 2010, a secondary analysis of three large randomised bisphosphonate trials including 14 195 patients concluded that subtrochanteric femoral fractures were very rare and statistically not associated with bisphosphonate use.12 However, these studies, did not assess individual fracture radiographs but, rather, relied on written reports, all of which were created many years before the recognition of the atypical fracture pattern as a distinct entity. Hence, although these studies indicate that subtrochanteric or diaphyseal femur fractures in patients receiving bisphosphonates are very rare, they do not provide definitive information on the potential association between bisphosphonate use and the occurrence of atypical fractures. The subtrochanteric location of these femoral fractures may offer potential insight into their biomechanical evolution. The theory of bisphosphonate-related severe suppression of bone turnover, with the development of a transverse fracture in the area of maximal weight-related stress, is supported by a number of bone biopsy studies2,4,13 but remains controversial due to the lack of clear causal evidence. In conclusion, the evidence supporting an association between bisphosphonate use and atypical fractures remains preliminary, with the failure of large epidemiological and observational studies to substantiate such an association. Certainly, these fractures are rare and their biomechanical evolution remains unclear. With all of this in mind, physicians should remember that bisphosphonates are highly beneficial in the management of osteoporosis and that their anti-fracture effects by far outweigh the risks posed by this rare, potential reaction. However, they should also be aware of the possibility of atypical femur fractures in patients receiving prolonged oral bisphosphonate therapy, and maintain a low threshold for investigating those who report otherwise unexplained thigh or groin pain. Atypical and typical osteoporotic fractures of the femur A: Radiograph demonstrating the characteristic appearance of an atypical femoral fracture: a transverse or oblique (< 30°) fracture line in an area of cortical thickening with a medial unicortical beak. The biomechanical theory of severe suppression of bone turnover with an insufficiency fracture and secondary cortical thickening at the area of maximal weight-related stress has been proposed. The patient had been receiving alendronate for 7 years before the spontaneous development of this fracture. B: Radiograph demonstrating a typical osteoporotic spiral fracture involving the diaphyseal femur.

Christian M Girgis MB BS(Hons) · Markus J Seibel MD, PhD, FRACP

Australia should support international bans on asbestos trade The adverse health effects of asbestos are well known, with all forms of asbestos recognised as human carcinogens, causing malignant mesothelioma, lung, laryngeal and ovarian cancers1 as well as the debilitating non-malignant diffuse lung disease, asbestosis, and pleural plaques. Although use, import and export of asbestos and asbestos-containing materials is banned in Australia and 51 other countries,2 an estimated 125 million people around the world are still exposed to asbestos in their home and work environments.3 Crocidolite (blue asbestos) and amosite (brown asbestos), two forms of asbestos that were heavily used in the past, are no longer in use. Chrysotile (white asbestos) accounts for 95% of the asbestos produced and used globally since 1990. There is no safe level of exposure to asbestos4 and no discernible threshold below which there is no risk of mesothelioma.5 Given the clear dangers, why are workers and their families in many parts of the world still being exposed to asbestos? Exposure comes from two main sources: residual asbestos-containing materials remaining in buildings constructed before the mid-1980s (when asbestos-containing cement sheet was removed from the market); and continuing mining and use of asbestos in some parts of the world. In Australia, the legacy of asbestos remains a problem. In most cases, asbestos is in a non-respirable form, and is not a hazard to human health if undisturbed. However, if damaged, it can become friable and change to a respirable form. The issues central to this global problem are education and research. Education about when asbestos exposure may occur, and how to avoid it, remains important. In this respect, the recent survey by Safe Work Australia6 is reassuring, with most tradespeople reporting awareness of asbestos-related health risks and demonstrating an understanding of how exposures occur. However, there was a general lack of understanding about which materials may contain asbestos, and there are no data on the level of awareness among people doing their own renovations. Asbestos will be with us for decades, so targeted and contextually appropriate education programs for at-risk populations are required. The effects of such programs should be monitored for their impact on risk, mortality and morbidity. As most of the people who will die from asbestos-related cancers in Australia already have asbestos in their lungs, research aimed at preventing or curing these cancers is also vital. Globally, the major problem is with continued mining and use of asbestos, with over 2 million tonnes produced in 2008.7 Developing countries, especially in Asia and Eastern Europe, are mining or importing asbestos for domestic use, and now account for the majority of the world’s exposure to asbestos. Thousands, if not millions, of people are likely to die in these countries as a result of continued asbestos exposure.8 Chrysotile is the only form of asbestos that is being traded in the 21st century; it is mostly used in the manufacture of asbestos cement sheets and pipes. There is a mistaken belief that this form of asbestos is less harmful than other forms, but overwhelming scientific evidence refutes this assertion.9 All forms of asbestos are classed as human carcinogens by the United States Environmental Protection Agency, and cancer is seen in workers who have only been exposed to chrysotile asbestos.9 There is also a mistaken view that chrysotile can be handled safely. Reports from the National Public Health Institute of Quebec show a failure to achieve “controlled use”, even in Quebec. In many developing countries, exposure is uncontrolled, and education of workers is, at best, minimal, and often non-existent. Tobacco smoking is also widespread in Asia, and is synergistic with chrysotile in increasing the risk of lung cancer. International organisations such as the World Health Organization and the International Labour Organization have called for a global ban of all forms of asbestos, with the goal of eliminating asbestos-related diseases.10 The Collegium Ramazzini, an international academic society independent of commercial interests that examines critical issues in occupational and environmental health, has just renewed its call for such a ban. This could, in part, be achieved via the Rotterdam Convention (http://www.pic.int), an international treaty intended to regulate global trade in chemicals that have been banned or severely restricted because of the hazards they pose to human health or the environment. The Convention was enacted in 2004, and 131 nations, including Australia, are current partners. The goal of the Convention is to protect the world’s most vulnerable countries from importing hazardous pesticides or regulated chemicals without prior knowledge or consent. Repeated efforts to include chrysotile asbestos under the Rotterdam Convention have failed, due to opposition from countries which mine and manufacture asbestos, including Canada. The Canadian Medical Association, Canadian Cancer Society and Canadian Public Health Association oppose exporting asbestos to developing countries, yet their government officially condones this activity. We, personally and on behalf of our respective professional affiliations, call for Australia and Australians to strongly support the latest international effort to ban the mining and manufacture of all forms of asbestos; to increase efforts, at home and abroad, in effective education of the dangers of asbestos both in the workplace and in the environment; and urge our legislators to redouble their efforts to rid the world of asbestos-related diseases.

Peter D Sly MB BS, FRACP, DSc · Robin Chase MB BS, DPH, FAFOEM · John Kolbe MB BS, FRACP · Philip Thompson MB BS, FRACP · Leena Gupta MB BS, MPH, FAFPHM · Mike Daube BA(Hons), HonDSci · Ian Olver MD, FRACP · Deborah Vallance BMedSci, MB BS, MPH