Volume 191 Issue 6

We have a tool for absolute risk assessment — now we need a robust implementation program In March 2009, the National Vascular Disease Prevention Alliance (NVDPA), a consortium of Diabetes Australia, Kidney Health Australia, the National Heart Foundation of Australia, and the National Stroke Foundation, released evidence-based guidelines for assessing absolute cardiovascular risk.1 The guidelines are for use by health professionals who assess patients’ cardiovascular risk, primarily general practitioners. The risk charts that accompany the guidelines differ somewhat from the New Zealand risk charts,2 which are commonly used in Australia. Both the Australian and NZ charts are based on the Framingham Heart Study.3 The Australian cardiovascular risk charts are separated at the broader level into people with and without diabetes, rather than into men and women. In addition, systolic, but not diastolic, blood pressure is included because it is the stronger determinant of future events. The charts extend to upper cut-off points of 179 mmHg for systolic blood pressure and 7.5 mmol/L for total cholesterol level, respectively. The NVDPA guidelines also have an online risk calculator (http://www.cvdcheck.org.au). The new NVDPA guidelines and charts have the advantage of taking into account other drivers of practice in Australia, such as the Royal Australian College of General Practitioners’ Guidelines for preventive activities in general practice,4 and eligibility for Pharmaceutical Benefits Scheme subsidies for statins. Absolute risk assessment maximises the effectiveness of prediction of risk of future cardiovascular disease (CVD) events in people apparently free of such disease. This is because the underlying equations acknowledge fundamental epidemiological principles: risk depends on the range of independent risk factors and, for biomedical factors, risk typically increases in a log–linear manner above ideal levels (systolic blood pressure and total cholesterol level, 115 mmHg and 3.8 mmol/L, respectively).5 The present, somewhat arbitrary, definitions of hypertension and hypercholesterolaemia as ≥ 140/90 mmHg and ≥ 5.5 mmol/L, respectively, are fundamentally flawed, and most people who have CVD events have a clustering of risk factors with only modest abnormalities. If relative risk reduction with an intervention is relatively constant (the usual case), use of the intervention in those at higher absolute risk leads to greater absolute risk reduction and net benefit, thus also maximising cost-effectiveness. All absolute risk tools share some problems. As they are derived from large population studies, they are better at rank-ordering risk in subgroups and less precise in an individual. However, individual risk assessment may be refined (particularly in those initially assessed to be at intermediate risk) by measuring biomarkers or by imaging,6 and probably more so in the future, as more evidence becomes available. Other factors that might also be added to future algorithms include anthropometric measures (of these, waist circumference or waist : hip ratio appears more predictive than body mass index), a family history of premature atherosclerotic disease, and measures of socioeconomic deprivation.7 The NVDPA guidelines acknowledge that the Framingham risk equation may underestimate risk if these factors are present. The major determinant of CVD risk is increasing age, and it is also likely that equations specific for various age groups will become available. Particularly among younger people, this will improve identification of those with greater modifiable risk. Ideally, risk equations should be developed and validated in the local population. In Australia, algorithms for the general population have been developed from the Busselton8 and Dubbo9 studies. These are important contributions, although the relatively narrow endpoint (in Busselton) and the cohort age (in Dubbo) limit their application. How best can the NVDPA tools be used by practising clinicians? The first step is to identify high-risk groups. These include people with one or more of the following: prior CVD events, peripheral arterial disease, diabetes and age ≥ 60 years, chronic kidney disease, and familial hypercholesterolaemia. Such people should be treated accordingly and do not need absolute risk assessment. In all others, absolute risk assessments should commence at age 45 years, or 35 years for Aboriginal and Torres Strait Islander people, and be repeated at intervals reflecting the initial level of risk.1 An example of how to incorporate absolute cardiovascular risk assessment into management is given in the Box. What we now need is a robust implementation program. This makes economic sense. Recently, the National Health Service Health Check program was released in the United Kingdom.10 Everyone between 40 and 74 years, not already diagnosed with heart disease, stroke or kidney disease, will be invited, once every 5 years, to have their risk assessed using an absolute risk tool, and given support and advice to help them reduce or manage their risk. Analyses showed that this program would be very cost-effective compared with other accepted health interventions. The modelled cost-effectiveness ratio of this UK program is only £2480 per quality-adjusted life-year gained. Presently, in Australia, a Medicare item number supports a single health check for those aged 45–49 years. Although cost-effectiveness analyses are sensitive to the local health care system, the UK data strongly suggest that the current Medicare item number could be expanded, and other systems-based approaches implemented, to ensure that ongoing primary care risk assessments are supported, and that people at higher risk receive lifestyle and appropriate medical management. Implementation would be most likely to be effective if decision-support tools and recall mechanisms were used and incorporated into prescribing linked to electronic health records. Accompanying materials that appropriately communicate concepts of risk to patients would also be useful. The NVDPA is now developing a single CVD risk-management guide that will integrate the various specific risk-factor guides and make it easier to manage patients according to their absolute risk status. Absolute risk assessment does not replace the need to base all approaches to CVD prevention on lifestyle change. Studies have clearly shown the value of this, whether or not individuals are receiving blood-pressure or lipid-lowering therapies.11 However, absolute risk assessment leaves behind time-hallowed approaches based on individual risk factors, treated in silos, and often “dichotomised” to be regarded as “normal” or “abnormal”. It moves us forward to a more rational and effective paradigm for preventing our major health problem. How to incorporate absolute risk assessment into management using the Australian cardiovascular risk charts (the “People without diabetes” section of the charts is reproduced below) Example: Two women with similar risk profiles, but different ages Both women are smokers, without diabetes, with systolic blood pressure, 140 mmHg; total cholesterol : high-density lipoprotein cholesterol (TC : HDL) ratio, 7.2 mmol/L; and body mass index, 27 kg/m2. A is 46 years old and estimated to have a low risk (5%–9%) of developing cardiovascular disease (CVD) within 5 years. However, if she continues to smoke and to have a high TC : HDL ratio, she will place herself at high risk of prematurely developing CVD as she gets older. The chart can be used to demonstrate this to her. The priority intervention should be lifestyle advice, including smoking cessation, physical activity and healthy eating. B is 66 years old and estimated to be at high risk (20%–24%) of having a CVD event within 5 years. As a high priority, she should receive advice about smoking cessation and other lifestyle changes, as well as statin therapy. How to use the risk chart 1. Identify the chart relating to the person’s sex, diabetes status, smoking history and age. The charts should be used for all adults aged 45–74 years (and all Aboriginal and Torres Strait Islander adults aged 35 years or older) without known history of CVD or already known to be at high risk. 2. Within the chart, choose the cell nearest to the person’s age, systolic blood pressure (SBP) and total cholesterol (TC):HDL ratio. For example, the lower left cell contains all non-smokers without diabetes who are 35–44 years and have a TC:HDL ratio of less than 4.5 and a SBP of less than 130 mm Hg. 3. The colour of the cell that the person falls into provides their 5-year absolute cardiovascular risk level (see legend above for risk category). People who fall exactly on a threshold between cells are placed in the cell indicating higher risk. Charts are based on the NVDPA’s Guidelines for the assessment of absolute cardiovascular disease risk and adapted with permission from New Zealand Guidelines Group. New Zealand Cardiovascular Guidelines Handbook: A Summary Resource for Primary Care Practitioners. Second edition. Wellington, NZ: 2009. www.nzgg.org.nz. These charts are taken from Absolute cardiovascular disease risk assessment – quick reference guide for health professionals. © 2009 National Heart Foundation of Australia. Reproduced with permission. No further reproduction is allowed.

Andrew M Tonkin MD, FRACP, FCSANZ · Andrew N Boyden MPH, FRACGP · Stephen Colagiuri FRACP

New guidelines and a multidisciplinary approach have the potential to help patients in need while minimising inappropriate use of opioids With an estimated community prevalence of about 20%, chronic non-malignant pain represents a significant but neglected and often poorly managed problem in Australia. In 2007, the cost of chronic pain to the community was estimated at $34 billion, which included burden of disease and productivity costs, each accounting for one-third of the total, and one-fifth ($7 billion) attributed to health system costs.1 Its prevalence and associated costs will rise as the population ages. The causes of chronic non-malignant pain are many, including rheumatic disorders, injuries and musculoskeletal degenerative disorders, and vary greatly with age, sex and other demographic characteristics. Many doctors currently approach such pain from a narrow biomedical perspective. This too often defaults to the use of opioids under pressures including time constraints, patient demands, and limited access to supports such as pain clinics and physical therapies. The introduction of sustained-release prescription opioids in Australia two decades ago promised a new era in chronic pain management. These agents were preferred because they offered prolonged analgesia with a potentially lower risk of dependence and drug-seeking behaviour. Previously, short-acting opioids had often been prescribed, causing problems when peak effects of analgesia and euphoria alternated frequently with troughs marked by pain and opioid withdrawal. This created conditions conducive to dose escalation and the eventual development of dependence. The shining promise of the sustained-release prescription opioids has been dulled by two main problems. First, the long-term effectiveness and net benefit of opioids in the management of patients with chronic non-malignant pain remain uncertain, reflecting the biopsychosocial complexity of the underlying conditions and the difficulties of performing clinical trials in such heterogeneous populations.2 Second, increasing consumption of sustained-release prescription opioids has been accompanied by some disturbing developments, first reported from the United States. In 2000, drug overdose deaths from prescription opioids, especially from unsanctioned use, began to outnumber deaths from heroin and cocaine.3 Between 1997 and 2007, admissions for treatment of “abuse” rose by 456% for opioid analgesics and 5% for heroin.4 Australia may be starting to follow these US trends, with substantial increases in consumption of oral prescription opioids since 1990,5 and reports of diversion, injection and related harms.6 However, the extent of inappropriate opioid prescribing and of unsanctioned opioid use in Australia cannot currently be determined. Our information systems are not standardised across jurisdictions, are unable to capture all prescriptions (both private and funded by the Pharmaceutical Benefits Scheme), and are not available to intending prescribers and pharmacists. Three overlapping groups — patients with chronic non-malignant pain, patients with malignant pain, and illicit users (of heroin or prescription opioids) — form a potential common market for opioids, with flow-on effects if any group is inadequately managed. The idea of a continuum between opioid use for pain management and addiction underpins the idea of “universal precautions in pain medicine”.7 Inappropriate prescription can lead to problematic use and opioid dependence. The heroin shortage that started in 2000 in Australia was followed by increasing injection of prescription opioids, especially in rural areas and jurisdictions where heroin was scarcest.8 Increasing demand for prescription opioids may arise where there is unmet demand for opioid substitution treatment with methadone or buprenorphine. People on low incomes may be tempted to request and on-sell prescription drugs to the black market as demand and prices increase. These considerations underpin the desirability of a broader biopsychosocial framework for the assessment of patients with chronic non-malignant pain, and a greater role for non-pharmacological interventions. Such interventions are scarce and underfunded in primary care. Australia has the most developed training program for pain medicine worldwide, but there are too few specialists and there is great demand for pain clinics. In an effort to bring these complex issues to the fore, the Royal Australasian College of Physicians (RACP) has released a prescription opioid policy;9 the Box contains a summary of its recommendations. Reflecting the complex nature of the subject, the report was prepared by an interdisciplinary group, including representatives from the RACP, the Royal Australian College of General Practitioners, the Royal Australian and New Zealand College of Psychiatrists and the Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists. The challenge is to provide a better balance between two, sometimes competing, objectives — encouraging more appropriate opioid prescription for patients with chronic non-malignant pain while reducing unsanctioned use of opioids, whether by patients or illicit users. No single health discipline can overcome these complex problems, but a truly multidisciplinary approach has the potential to achieve great advances. The current situation not only results in frustration for patients and families, but also undermines the good standing of the medical profession. The present unhappy cocktail includes patients with chronic, complex painful conditions; doctors who lack succinct uniform guidelines, real-time prescription monitoring information and ready access to relevant specialist advice; and a setting where authorities must minimise diversion of prescription opioids. In 2008, unmet demand for opioid substitution treatment was estimated to exceed the 39 000 patients then in such programs.10 Better tailoring of such treatment to also meet the needs of people dependent on pharmaceutical opioids, many of whom have never previously sought help, may attract and retain more patients in effective treatment. This would most likely decrease the demand for black-market prescription opioids. Australia has a unique opportunity to improve management of patients with chronic non-malignant pain and people who become dependent on opioids; to reduce inappropriate prescribing of opioids; and to avoid the problems that have bedevilled the US. The most important step required is establishing a group with sufficient authority to achieve wide consensus on an action plan and then implement and coordinate national change across jurisdictions, professions and disciplines (especially general practitioners and pharmacists). As most management of chronic non-malignant pain occurs in general practice, little will be achieved unless and until GPs are provided with more support and better linkages to critical specialties. Summary of recommendations of the Royal Australasian College of Physicians report9 1. Establish a national expert advisory group to develop a coordinated approach to implementing the recommendations below, to improve management of chronic non-malignant pain and reduce problematic use of pharmaceutical opioids. 2. Develop guidelines for management of chronic non-malignant pain appropriate for and accepted by general practitioners, integrating non-pharmacological elements of treatment with pharmacological approaches within a biopsychosocial framework, and providing widely accepted standards for audit and feedback. 3. Enhance clinical practice, with improved support for GPs and better linkages to relevant specialties, especially pain medicine and addiction medicine. 4. Improve information systems, with one national, web-based system that includes private and Pharmaceutical Benefits Scheme prescriptions and provides information for prescribers and pharmacists in real time. 5. Standardise regulation and control across jurisdictions. 6. Minimise unmet demand for opioid substitution therapy, and revise it for people dependent on pharmaceutical opioids to decrease the demand for black-market prescription opioids. 7. Improve integration of College training programs in the fields of pain medicine, addiction medicine, psychiatry and general practice. 8. Increase applied research to reduce gaps in knowledge and improve health service delivery.

Alex D Wodak FRACP, FAChAM, FAFPHM · Milton L Cohen MD, FRACP, FFPMANZCA · Malcolm D H Dobbin PhD, FAFPHM, MPH · Richard A Hallinan BMed, FAChAM · Mary Osborn MPubHlth

Objective: To describe cardiovascular disease (CVD) risk management in Indigenous primary health care.Design, setting and participants: Review of 1165 randomly selected case records of Indigenous Australian adults, aged ≥ 18 years, regularly attending eight health services in diverse settings in New South Wales, Queensland and Central Australia, October 2007 – May 2008.Main outcome measure: Adherence to CVD risk screening and management guidelines, especially with respect to overall or absolute CVD risk.Results: More than half the people in the sample (53%) were not adequately screened for CVD risk according to national recommendations. Underscreening was significantly associated with younger age, less frequent attendance, and lower uptake of the Medicare Health Assessment. Of the sample, 9% had established CVD, and 29% of those aged ≥ 30 years were classified as high risk according to the 2004 National Heart Foundation of Australia (NHFA) adjusted Framingham equation. Of those with CVD, 40% (95% CI, 30%–50%) were not prescribed a combination of blood pressure (BP) medicines, statins and antiplatelet agents, and 56% (95% CI, 49%–62%) of high-risk individuals without CVD were not prescribed BP medicines and statins. For high-risk individuals not prescribed BP medicines or statins, 74% (95% CI, 64%–84%) and 30% (95% CI, 23%–39%) respectively, did not meet 2004 NHFA criteria for prescribing of these medications, and of those already prescribed BP medicines or statins, 41% (95% CI, 36%–47%) and 59% (95% CI, 52%–66%) did not meet respective guideline targets.Conclusions: These management gaps are similar to those found in non-Indigenous health care settings, suggesting deficiencies across the health system. Prescribing guidelines which exclude many high-risk individuals contribute to suboptimal management. Guideline reform and improved health service capacity could substantially improve Indigenous vascular health.

David P Peiris MB BS, FRACGP, MIPH · Anushka A Patel MB BS, PhD, FRACP · Alan Cass MB BS, FRACP, PhD · Michael P Howard RN, MHN, MPH · Maria L Tchan BN, MPH · John P Brady BScApp · Joanne De Vries DipPHC · Bernadette A Rickards RN, MPH · Della J Yarnold MB · Noel E Hayman MB BS, MPH, FAFPHM · Alex D Brown BMed, MPH, FCSANZ

Objective: To investigate trends in the incidence of adenocarcinoma (AC) of the oesophagus in New South Wales, factors associated with a diagnosis of AC, and factors associated with survival of patients with AC.Design and setting: We examined all cases of invasive oesophageal cancer recorded in the NSW Central Cancer Registry from 1972 to 2005. The Accessibility/Remoteness Index of Australia was used to assess geographical remoteness and the Index of Relative Socio-Economic Disadvantage to assess socioeconomic status.Main outcome measures: Incidence of AC; factors associated with diagnosis of AC and survival of patients with AC.Results: The overall incidence of oesophageal AC in NSW increased in both males and females (annual percentage change, 4.2% [95% CL, 2.7%, 5.8%] in males [1988–2005] and 4.3% [95% CL, 1.8%, 7.0%] in females [1983–2005]). A diagnosis of AC was significantly associated with being male (adjusted odds ratio [AOR], 4.37 [95% CL, 3.84, 4.98]; P < 0.001); a younger age at diagnosis (P trend < 0.001); having distant rather than localised disease spread (AOR, 2.12 [95% CL, 1.82, 2.48]; P < 0.001); higher socioeconomic status (P trend < 0.001); and living in an inner regional area (AOR, 1.26 [95% CL, 1.11, 1.43]; P < 0.001) or outer regional area (AOR, 1.19 [95% CL, 1.00, 1.41]; P = 0.05) compared with a major city. Early diagnosis of AC was associated with substantial improvement in survival outcomes: patients with metastatic disease at diagnosis had a three times greater risk of dying than those with localised AC at diagnosis.Conclusion: The incidence of AC is increasing in NSW. Possible contributing factors include increasing obesity, which is associated with increased incidence of gastro-oesophageal reflux disease. Survival may be improved by diagnosis at an earlier stage and changes in modifiable risk factors (eg, smoking, diet, exercise).

Efty P Stavrou PhD · Heather J McElroy MMedStat · Deborah F Baker MPH · Garett Smith BMed, MS, FRACS · James F Bishop MMed, MD, FRACP

Objective: To describe demographic and clinical characteristics of patients residing in Victoria who were diagnosed with multidrug-resistant tuberculosis (MDR-TB) during the period 1 January 1998 to 31 December 2007.Design, setting and patients: Retrospective review of Victorian Department of Health data on laboratory-confirmed cases of MDR-TB for the period 1998–2007.Main outcome measures: Age, sex, country of birth, time between arrival in Australia and notification of TB, residency status, site of disease, and treatment period and outcome.Results: From 1998 to 2007, 31 patients who resided in Victoria were diagnosed with MDR-TB. The median age of patients was 27 years, most patients were born overseas, and more than half were full-time students. The median time between arrival in Australia and notification of TB was 2 years, and 24 patients were notified to the Department within 5 years of arrival. Twenty patients had pulmonary disease; in 12 of these patients, sputum was smear-positive for acid-fast bacilli. The median treatment period for patients who completed treatment was 22 months.Conclusions: The number of patients diagnosed with MDR-TB per year increased during the period 1998–2007. If sustained, this increase will have important implications for public health policy and planning.

Caroline J Lavender BA, BSc(Hons) · Lynne K Brown DipAppSci · Paul D R Johnson MB BS, PhD, FRACP

Objective: To examine the effect of the level of patient copayment on the rate of purchase of inhaled corticosteroids (ICS) by patients with obstructive lung disease.Design and setting: Cross-sectional study of records of all prescriptions for ICS dispensed to general and concessional beneficiaries aged 15 years or over in the period January 2003 to December 2006. Data were obtained from the Pharmaceutical Benefits Scheme, which subsidises medication costs for all Australians.Main outcome measures: The number of prescriptions for ICS dispensed to government concession card holders compared with the number dispensed to general beneficiaries, expressed as a rate ratio.Results: ICS prescriptions were dispensed to over 1.6 million people during the study period. Concession card holders were dispensed ICS prescriptions at a higher rate than general beneficiaries, both overall (43.7 v 9.1 ICS prescriptions per 100 person-years) and in all population subgroups. After adjusting for age, sex, remoteness category and socioeconomic status, people holding a concession card were dispensed over 2.5 times the number of ICS prescriptions (alone or in combination with a long-acting β2-agonist) compared with general beneficiaries. Similar patterns were seen after adjusting for differences between the two groups in the prevalence of obstructive lung disease.Conclusions: As the patient copayment for general beneficiaries is over six times higher than for concession card holders, our findings imply that cost is a barrier to the purchase of ICS prescriptions for obstructive lung disease, independent of socioeconomic status.

Rosario D Ampon BSc, MAppStat · Helen K Reddel MB BS, FRACP, PhD · Patricia K Correll BN, MPH, GradDipAppEpi · Leanne M Poulos BMedSc(Hons), MPH(Hons) · Guy B Marks PhD, FRACP, FAFPHM

Objective: To evaluate the management of cardiovascular disease (CVD) risk in Australian general practice.Design, setting and participants: National cross-sectional survey of 99 Australian general practitioners participating in the Bettering the Evaluation and Care of Health (BEACH) program. Data on 2618 consecutive adult patients presenting to the participating GPs over a 5-week period from September to October 2006 were analysed.Main outcome measures: Proportions of patients screened, treated and reaching targets according to (1) current Australian CVD risk guidelines and (2) overall or absolute CVD risk.Results: Blood pressure (BP) had not been recorded for 13% of the sample. Of 1400 patients not prescribed antihypertensive medication, treatment was indicated for 8%. Of 821 patients already prescribed antihypertensive medication, 59% were achieving target BPs. Data on low-density lipoprotein (LDL) cholesterol levels were not available for 53% of the 2175 patients who should have had lipid screening according to the guidelines. Of 624 patients not prescribed a statin, treatment was indicated for 41%. Of 368 already prescribed a statin, 62% were achieving target LDL cholesterol levels. Sufficient data for calculation of absolute risk had been recorded for 74% of the 1736 patients for whom such calculation was recommended by the guidelines. The remaining 26% either had at least one required variable unmeasured (20%) or missing from the data collection (6%). For those at high absolute CVD risk (without established disease) and those with established CVD, 23% and 53%, respectively, had been prescribed both antihypertensive medication and a statin.Conclusions: Gaps between guideline recommendations and practice in recording and managing BP were relatively low compared with gaps for lipids. When stratified by absolute risk, patients at high risk of a cardiovascular event were found to be substantially undertreated.

Ruth J Webster BMedSc(Hons), MB BS(Hons), MIPH(Hons) · Emma L Heeley BSc(Hons), MSc, PhD · David P Peiris MB BS, FRACGP, MIPH · Clare Bayram BAppSc(HIM)(Hons) · Alan Cass MB BS, FRACP, PhD · Anushka A Patel MB BS, FRACP, PhD

Objective: To determine whether a surveillance program including clinical breast examination (CBE) and three screening modalities (magnetic resonance imaging [MRI], high-resolution ultrasound [U/S] and mammographic x-ray [MMX]) was feasible, and whether it could improve detection of pathological lesions in young women at high risk of developing breast cancer.Design, setting and participants: Western Australian women aged 50 years or under at high risk of developing breast cancer were recruited to our study. For a 2-year period, they were offered breast MRI and U/S scans in addition to their annual MMX and CBE. Our study was conducted between June 2002 and October 2005.Main outcome measures: Number and type of cancerous or precancerous lesions; recall rates after screening; comparative sensitivity of screening modalities.Results: Of 102 women approached, 72 agreed to participate. Fifteen lesions were detected, of which three were significant: a metastatic papillary cancer in an axillary lymph node, a borderline lesion (multiple papillomatosis with atypia), and a papilloma. All 15 lesions were visible on MRI, and four were detected by MRI only. Only one lesion was visible on all three imaging modalities. Nothing significant was detected by CBE. The recall rate after MRI scans fell from 9/72 (12.5%) in the first year to 5/67 (7.5%) in the second year.Conclusion: Our study gave valuable experience in a team approach to screening MRI, and showed that MRI can detect more lesions than MMX or U/S in women at high risk of developing breast cancer. Screening U/S may not add value to MMX and MRI screening, and we suggest a single oblique-view MMX may be used in some cases.

Christobel M Saunders MB BS, FRCS, FRACS · Gudrun Peters FRANZCR · Glenys Longman RN · Jacqueline Thomson MB ChB, FRANZCR · Donna Taylor MB BS, FRANZCR · Jianmin Hua BSc · Michelle Bennett MB ChB, FRANZCR · Elizabeth Wylie MB BS, FRANZCR · Jack Goldblatt MB BS, MD, FRACP · Arlene Chan MB BS, FRACP, MMed · James Anderson MB BS, FRANZCR

A systematic, integrated national approach is needed to implement 2006 Australian guidelines for management of acute coronary syndromes (ACS). Clinical outcomes can be improved by closing the current gaps between evidence and practice. In 2007, the National Heart Foundation of Australia, the Cardiac Society of Australia and New Zealand, and the Australasian College for Emergency Medicine held a national forum to identify current gaps in ACS management and priority strategies to improve outcomes. Consensus recommendations were based on evidence and expert opinion. Prompt reperfusion for patients with ST-segment-elevation myocardial infarction should be ensured by establishing protocols for single-call activation of primary percutaneous coronary intervention, or, where unavailable, enabling health care workers to initiate thrombolysis. Accuracy of risk stratification of non-ST-segment-elevation ACS (NSTEACS) should be improved using clinical pathways that integrate ambulance, medical and nursing care. Rates of early invasive management for patients with high-risk NSTEACS should be increased using efficient systems for transfer to revascularisation facilities. All patients with an ACS should be referred to rehabilitation and secondary prevention programs, including alternative models of care where appropriate. Equal access to recommended care for all Australians with an ACS — including those in rural, remote and Aboriginal and Torres Strait Islander communities — should be achieved by improving workforce capacity in under-resourced regions and ensuring access to third-generation fibrinolytic agents, defibrillation, timely essential pathology tests and invasive revascularisation facilities. National standards for data collection and clinical outcomes should be established, and performance should be monitored.

on behalf of the National Heart Foundation ACS Implementation and Advocacy Working Group

Tight glycaemic control reduces the risk of development and progression of organ complications in people with type 1 or type 2 diabetes. In this position statement, the Australian Diabetes Society recommends a general target glycated haemoglobin (HbA1c) level of ≤ 7.0% for most patients. This position statement also provides guidelines for the individualisation of glycaemic targets to a tighter or lesser degree, with a recommended target HbA1c level of ≤ 6.0% in some people, or up to ≤ 8.0% in others. Individualisation of the HbA1c target is based on patient-specific factors, such as the type of diabetes and its duration, pregnancy, diabetes medication being taken, presence of cardiovascular disease, risk of and problems from hypoglycaemia, and comorbidities. Management of diabetes also includes: adequate control of other cardiovascular risk factors, including weight, blood pressure and lipid serum levels; antiplatelet therapy; and smoking cessation.

N Wah Cheung MB BS, FRACP, PhD · Jennifer J Conn FRACP, MClinEd, BSc(Hons) · Michael C d’Emden MB BS, PhD, FRACP · Jenny E Gunton MB BS, FRACP, PhD · Alicia J Jenkins MD, FRACP, FRCP · Glynis P Ross MB BS(Hons), FRACP · Ashim K Sinha MB BS(Hons), MD, FRACP · Sofianos Andrikopoulos PhD · Stephen Colagiuri MB BS(Hons), FRACP · Stephen M Twigg MB BS(Hons), PhD, FRACP

Our public health system, addicted to increasing centralisation and regulation, is pushing our everyday work environment beyond the point of sustainability — it has become too complex. Like an ecosystem grown too complex to resist sudden environmental change, public health organisations have become “brittle”, unable to respond to changing conditions. Another bureaucratic restructuring, such as recommended by the Garling report, can only be self-defeating. It is time for us to design systems small enough, and therefore resilient enough, to meet tomorrow’s challenges.

Hans Peter Dietz MD, PhD, FRANZCOG

Although glycated haemoglobin (HbA1c) has become the key biochemical marker of long-term glycaemic control, analytical method-dependent differences in results can occur when haemoglobin variants are present or HbA1c is reduced by decreased red cell survival. When the measured HbA1c level is discordant with the patient’s blood glucose measurements and clinical status, fructosamine is an alternative biochemical marker that can provide a more accurate estimate of the glycaemic control and enable clinicians to appropriately manage patients. Clinical recordA 65-year-old, centrally obese man (body mass index, 32.7 kg/m2) with a 23-year history of type 2 diabetes mellitus was referred to a diabetes clinic in January 2008 for stabilisation of his blood sugar levels. His diabetes was complicated by ischaemic heart disease, peripheral vascular disease, hypertension, dyslipidaemia, and stage 3 chronic kidney disease. His glycated haemoglobin (HbA1c) level on referral was 11.0%, measured using an ion-exchange chromatography (IEC) method on a Bio-Rad Variant II analyser (Bio-Rad Laboratories, Sydney, NSW), and the laboratory fasting glucose measurement was 19.3 mmol/L (Box 1). Both these results were consistent with the patient’s home blood glucose measurements (> 10 mmol/L). On presentation, the patient’s medication included human mixed insulin (Mixtard 30/70; Novo Nordisk, Sydney, NSW) (80 units before breakfast and 75 units before dinner), as well as simvastatin, aspirin, clopidogrel, diltiazem, ramipril, frusemide, omeprazole, bisoprolol, irbesartan and glyceryl trinitrate. The insulin regimen was changed to a basal-bolus regimen of insulin aspart and insulin glargine, which was titrated weekly on the basis of home blood glucose measurements. After 6 weeks, the patient’s HbA1c level had decreased to 5.8%, which appeared to be inconsistent with the home blood glucose measurements and the laboratory fasting glucose measurement (15.1 mmol/L). This change in HbA1c level coincided with the implementation of a modified method (“NU”) on the Bio-Rad Variant II analyser. Haemoglobin (Hb) studies (electrophoresis and chromatography) demonstrated an abnormal Hb variant interfering with the HbA1c measurement. The patient’s fructosamine level was tested and the result indicated improved glycaemic control, but not to the extent suggested by the HbA1c level. A week after the fructosamine measurement, the HbA1c measurement was repeated with a Siemens DCA 2000 analyser (Siemens, Melbourne, Vic) using an immunoassay (IA) method, which is less likely to be influenced by Hb variants. The result was congruent with the fructosamine estimation of the glycaemic control (Box 1). On subsequent visits, the patient’s HbA1c level was measured with a different IEC method on a Bio-Rad D-10 analyser (Bio-Rad Laboratories, Sydney, NSW), from which a substantially higher result was obtained (Box 1). A further fructosamine measurement (280 μmol/L) suggested the glycaemic control was better than the HbA1c results now indicated. To investigate the effect of the Hb variant on the different HbA1c assays, the patient’s 9 December 2008 sample was analysed using the different analytical systems available locally (Box 1). The highest (9.0%) and lowest (4.4%) HbA1c results were obtained from IEC methods on different analysers from the same supplier. Before the modification of the Bio-Rad Variant II method, there was incomplete separation of the Hb variant and HbA1c peaks (Box 2, A). After implementation of the modified method, the separation of the Hb variant and HbA1c peaks was much more distinct (Box 2, B and C). The instrument software integrates only the one HbA1c fraction or peak and therefore underestimates the HbA1c level by about 50%. The Bio-Rad D-10 chromatogram (Box 2, D) is similar in appearance to the chromatogram from the original Bio-Rad Variant II method (Box 2, A). The range of HbA1c values obtained with the affinity chromatography (AC) and IA methods spanned a range from 6.8% to 7.9% (Box 1); this variation is within the anticipated interlaboratory performance. To avoid such variation, one analytical method should consistently be used for monitoring longitudinal changes. The patient’s Hb variant was characterised as a heterozygote for the Hb Athens-Georgia mutation by a reference laboratory (Southern Cross Pathology Australia, Melbourne, Vic). This is a very rare and clinically silent variant detected in Caucasians where only one β-chain is affected,1,2 and, depending on the separation method, it can produce two peaks on the chromatogram, as was the case with the modified Bio-Rad Variant II NU method (Box 2, B). DiscussionThis case illustrates some of the caveats associated with measuring glycaemic control. A multifactorial approach is required to achieve optimal glycaemic control, as failure to recognise the true state of control might result in inappropriate clinical management decisions and less than optimal patient care. The rate of HbA1c formation is proportional to the average blood glucose concentration over the life span of red blood cells (about 120 days). Methods used to measure HbA1c are divided into the three categories of IEC, AC and IA. In the 2008 Royal College of Pathologists of Australasia Quality Assurance Program (http://www.rcpaqap.com.au), 59% of participants used IA, 30% used IEC and 11% used AC methods, performed on 29 different commercial platforms. About 40% of all HbA1c measurements were performed with point-of-care instruments that use either IA or AC methods. Interference from abnormal Hb variants can lead to falsely elevated or lowered HbA1c results with IEC methods. AC methods are the least affected by Hb variants, as the method separates all glucose-modified Hb molecules from non-modified molecules, and calculates the HbA1c value from the total glycated Hb result.3-5 More than 1300 Hb variants have been identified,2 and about half of these are clinically silent.4 An HbA1c level < 6% or > 15% in patients with diabetes can often be due to Hb variant interference.3,6 The prevalence of Hb variants is highest in Mediterranean regions, Africa and Asia, particularly India and Pakistan. IA methods are only affected by Hb variants where the first 4–10 amino acids of the Hb β-chain are altered, and the IA antibody is unable to bind.7 Elevated levels (> 10%) of HbF falsely lower HbA1c results in IA methods.7 HbF levels are normally < 1%, but increased levels occur in hereditary conditions (β-thalassaemias, sickle cell anaemia and congenital aplastic anaemia), late pregnancy, in some patients with abnormal Hb variants, and in neonates.5 As well as recent blood transfusions and abnormal Hb variants, reduced red cell survival (as occurs in haemolytic anaemia, haemorrhage, iron deficiency anaemia, end-stage renal disease, patients on haemodialysis,3 thalassaemias or sickle cell syndromes6) is another cause of falsely low HbA1c results with all analytical methods, as a consequence of less available time for non-enzymatic glycation to occur. Fructosamine measurement is an alternative method for monitoring glycaemic control in patients with reduced red cell survival, and provides an index of glycaemia over the preceding 2–3 weeks.6 Recent studies, including a position statement from the American Diabetes Association, have suggested that simultaneous measurement of HbA1c and fructosamine might complement one another and may provide more useful clinical information than HbA1c alone.8,9 However, unlike with HbA1c, to date there are no published accepted treatment targets for fructosamine, nor are the different fructosamine measurement methods standardised. The most recent consensus statement on the standardisation of HbA1c measurement recommends that laboratories should report an HbA1c-derived average glucose or estimated average glucose (eAG) value alongside the HbA1c level.10 As the eAG is calculated from the HbA1c level, it will not assist in those patients whose HbA1c measurement is not accurate because of Hb variants or reduced red cell survival. The HbA1c result and the eAG should correlate with the patient’s glucose measurements and clinical status. If they are discordant, the HbA1c result should be rechecked using an alternative analytical method that is less susceptible to interference from Hb variants. Alternatively, fructosamine measurement might be a useful adjunct in these cases. It may be prudent to rely more on glucose tests when there is uncertainty about long-term markers of glycaemic control, although the long-term markers may still be valuable for trend analysis. Considering current migration patterns, with more than half of the nearly 150 000 settlers arriving in Australia in the 2007–08 financial year coming from Africa, the Middle East and Asia,11 patients with Hb variants and decreased red cell survival will become more prevalent in the Australian population. This case emphasises the limitations of HbA1c assays in such patients and the importance of communication between clinicians and the laboratory when unexpected results occur. 1 Results from the various glycated haemoglobin (HbA1c) analytical systems and other laboratory measurements Date Analytical system Analytical method HbA1c* eAG (mmol/L) Glucose (mmol/L) Fructosamine (μmol/L)† 29 January 2008 Bio-Rad Variant II‡ (old method) IEC 11.0% 14.9 19.3 — 11 March 2008 Bio-Rad Variant II (new method) IEC 5.8% 6.6 15.1 — 1 April 2008 Bio-Rad Variant II (new method) IEC 4.9% 4.9 — — 3 May 2008 — — — — — 271 10 May 2008 Siemens DCA 2000§ IA 7.4% — — — 28 November 2008 Bio-Rad D-10‡ IEC 9.2% 12.0 7.8 280 9 December 2008 Bio-Rad Variant II (new method) IEC 4.4% 4.4 — 234 Bio-Rad D-10 IEC 9.0% 11.7 — Siemens DCA Vantage§ IA 7.5% 9.3 — Roche Integra¶ IA 7.7% 9.7 — Primus PDQ** AC 7.9% 10.0 — Bio-Rad in2it‡ AC 6.8% 8.2 — 20 January 2009 Bio-Rad in2it AC 7.3% — — 307 eAG = estimated average glucose. IEC = ion-exchange chromatography. IA = immunoassay. AC = affinity chromatography. * All HbA1c results are aligned to the National Glycohemoglobin Standardization Program (http://www.ngsp.org). † Reference range, 190–285 μmol/L. ‡ Bio-Rad Laboratories, Sydney, NSW. § Siemens, Melbourne, Vic. DCA Vantage is an upgraded model of the DCA 2000. ¶ Roche Diagnostics, Sydney, NSW. ** Primus Diagnostics, Kansas City, Mo, USA. 2 Chromatograms from Bio-Rad ion-exchange chromatography analysers* HbA1c values: A: 11.0% B: 4.9% C: 4.4% D: 9.0%. * Bio-Rad Laboratories, Sydney, NSW.

Goce Dimeski BSc · Carel J Pretorius MB ChB, FCPathChem(SA) · Anthony W Russell MB BS, FRACP, PhD · Stephen P Miller BSc · Robert J Bird MB BS, FRCP(Lon), FRCPA · Jacobus P J Ungerer MB BS, MMed(ChemPath), FRCPA

A 49-year-old man presented with verapamil toxicity complicated by hypotension and a junctional rhythm, in the context of deliberate self-poisoning with multiple drugs. The patient’s hypotension normalised following the early use of high-dose insulin euglycaemic therapy (HIET), without the need for additional vasopressors; it recurred when HIET was prematurely stopped, and again stabilised when HIET was recommenced. Consideration should be given to the early use of HIET in treating severe calcium channel blocker toxicity, rather than as a last resort after other therapies have failed. (MJA 2009; 191: 350-352) Clinical recordA 49-year-old man presented to a peripheral hospital emergency department 1–1.5 h after deliberately ingesting multiple medications: verapamil (unknown amount), controlled-release morphine sulfate (20 × 30 mg), diazepam (50 × 5 mg) and tramadol (15 × 200 mg). He was a smoker with a history of depression, ethanol misuse, chronic back pain, hypertension and a previous instance of deliberate self-poisoning with multiple drugs. At initial assessment, the patient’s vital signs were: temperature, 36.8°C; pulse, 84 beats/min; respiratory rate, 19 breaths/min; blood pressure (BP), 115/80 mmHg; oxygen saturation, 95% on room air; and Glasgow Coma Scale score, 14/15. He was drowsy, disorientated to time, and had 2 mm pupils that were equal and reactive. He had ataxia, dysarthria and was generally weak. His breath ethanol concentration was 0.172 mg%. Thirty minutes later, the patient was hypotensive (BP, 85/45 mmHg; pulse, 72 beats/min). He was treated with oxygen, 2 L intravenous (IV) 0.9% saline, a naloxone IV infusion (400 μg/h), and 10 mL IV 10% calcium gluconate. He was transferred to a tertiary referral centre and, on arrival (at 2.25 h after initial presentation), his BP was 85/45 mmHg, pulse was 64 beats/min, and an electrocardiogram (ECG) showed a junctional rhythm. Rapid sequence intubation (with propofol 40 mg + 20 mg IV and suxamethonium 100 mg IV) was performed for airway protection and ongoing management of haemodynamic instability, while metaraminol IV boluses (total, 0.7 mg) were administered. Activated charcoal (50 g) was given, and sedation was maintained with a propofol infusion. The patient remained hypotensive (BP, 75/45 mmHg; pulse, 56 beats/min) after intubation, so high-dose insulin euglycaemic therapy (HIET) was commenced at 3.5 hours after presentation. He was given dextrose (50 mL 50% glucose) and a 30 IU short-acting insulin IV bolus (~ 0.5 IU/kg), followed by a further bolus of 50 mL 50% glucose and a short-acting insulin IV infusion (30 IU/h) (Box 1). His BP improved to 110/70 mmHg at 4 hours, with a pulse of 82 beats/min and sinus rhythm on ECG, and he remained stable during transfer to the intensive care unit (ICU). The insulin infusion was abruptly stopped 5.5 hours after presentation, on arrival in the ICU. The patient’s hypotension subsequently recurred (systolic BP, 70 mmHg; pulse, 75 beats/min), prompting administration of 500 mL IV Gelofusine (a colloidal plasma volume substitute; B. Braun, Sydney, NSW) and commencement of an adrenaline IV infusion (20 μg/min). The insulin infusion (30 IU/h) was restarted at 8.5 hours, and his BP again stabilised (Box 1). The propofol IV infusion was gradually increased from 50 mg/h to 150 mg/h between 5.5 hours and 11.5 hours after presentation, and a noradrenaline IV infusion was commenced at 9.5 hours to maintain normotension. At 15.5 hours, pulmonary artery catheter measurements showed a high cardiac index (5.1 L/min/m2; reference range [RR], 2.5–4.0 L/min/m2) and a low systemic vascular resistance index (1047 dynes·s/cm5/m2; RR, 1900–2400 dynes·s/cm5/m2); the patient’s pulse was 85 beats/min and BP was 140/60 mmHg. HIET was continued and the patient remained haemodynamically stable. Adrenaline and noradrenaline were weaned off (at 17.5 hours and 23.5 hours, respectively), despite the propofol infusion rate being increased to 500 mg/h at 18.5 hours. Once sedation was withdrawn, the patient was extubated at 26.5 hours. Insulin was weaned over 5 h and discontinued at 30.5 hours; dextrose was stopped 1 h later. The patient was transferred to the observation ward and discharged well later that day, after psychiatric clearance. During treatment with HIET, the patient’s blood glucose levels were checked hourly and ranged from 6.6 mmol/L to 13.2 mmol/L (RR, 3.5–5.5 mmol/L). He received about 25 g/h of dextrose (mostly as 50% dextrose infusions). Potassium and magnesium levels were also serially monitored; the minimum potassium level was 2.7 mmol/L (RR, 3.5–5.0 mmol/L) at 8.75 hours, and the magnesium level troughed at 0.5 mmol/L (RR, 0.75–1.05 mmol/L) at 15 hours. These were corrected with a total of 200 mmol of potassium chloride and 20 mmol magnesium chloride. DiscussionHIET is an increasingly accepted therapy for calcium channel blocker (CCB) toxicity, but reports of its use are limited and it remains controversial. Indeed, the scarcity of severe CCB poisoning cases means that a randomised controlled trial of HIET may not be feasible.1 Treating clinicians who seek advice from clinical toxicologists are often hesitant about the high doses required and the potential for adverse effects. Such hesitancy is potentially harmful, as a hypotensive patient with a CCB overdose who otherwise appears well is at risk of abrupt lethal cardiovascular collapse.1 HIET is traditionally recommended after other therapies have failed.2,3 This case report aims to raise awareness of HIET for the treatment of CCB toxicity and supports its early use, rather than as a last resort.4 Verapamil binds the alpha-1 subunit of L-type calcium channels, preventing the intracellular influx of calcium.5 These channels are functionally important in cardiac myocytes, vascular smooth muscle cells, and islet beta cells.5 Verapamil’s cardiac toxicity results from excessive negative inotropy, negative chronotropy and negative dromotropy, characterised by myocardial depression, sinus bradycardia, and atrioventricular node blockade.4 Vascular smooth muscle tone is impaired, resulting in decreased afterload, systemic hypotension, and coronary vasodilation.5 Less well known are the metabolic effects of CCBs such as verapamil. Under the stress of the drug-induced shock state, the cardiac myocytes shift from using free fatty acids, their favoured “resting state” energy substrate, to carbohydrates.3,4 CCB toxicity also impairs the uptake of glucose and free fatty acids by cardiac myocytes3,4 and inhibits calcium-dependent mitochondrial activity required for glucose catabolism.3,4 Furthermore, insulin release is dependent on calcium influx into islet beta cells through L-type calcium channels.3,4 Thus, CCB toxicity can cause hypoinsulinaemia,3,4 which, in conjunction with CCB-induced insulin resistance, may lead to hyperglycaemia and a ketoacidotic state.6 Atropine, calcium boluses and infusions, glucagon, inotropes, vasopressors, and cardiac pacing have all been advocated for managing CCB toxicity, despite questionable efficacy.3,4,7-9 For instance, the evidence for glucagon is limited to small, non-blinded animal studies where no survival benefit or improvement in mean arterial pressure was shown, although heart rate improved in some cases.7 Rarely, heroic measures such as extracorporeal circulatory support and intra-aortic balloon counterpulsation have been successfully employed.5,10 HIET was first used to treat verapamil toxicity in humans in 1993, with a favourable outcome.6 Since then, in addition to animal studies, there have been nearly 70 cases reporting the beneficial use of HIET in humans, with an overall survival rate of 85%.8 However, to our knowledge, use of HIET in humans before the administration of glucagon or vasopressors has only been reported once.6 There have been some reports of HIET failure in treating CCB toxicity, although the dosing of insulin was low or uncertain, or it was used late.6,8 Early use of HIET may be more effective than HIET rescue therapy, as CCB-induced insulin resistance is greatest in the first 24 hours2 and the maximal haemodynamic benefit of HIET may not occur immediately.6 HIET may allow the heart to overcome metabolic starvation in CCB toxicity, which compounds the direct CCB impairment of myocardial contractility.3,4 Insulin increases glucose and lactate uptake by myocardial cells and improves function without increased oxygen demand.11,12 It also induces pyruvate dehydrogenase, hastening myocardial lactate oxidation, and helps clear the cytosol of glycolytic byproducts that impair calcium handling and cause diastolic dysfunction.3 Insulin promotes excitation–contraction coupling and contractility because enhanced glycolysis promotes increased sarcoplasmic reticulum-associated calcium ATPase activity and increased cytoplasmic calcium concentrations, and promotes calcium entrance into mitochondria and sarcolemma.3 HIET may be best used adjunctively with other measures such as catecholamines, for two reasons. First, insulin-mediated inotropy is not catecholamine-mediated, and is not affected by β blockers.3 Second, although insulin appears to improve myocardial contractility, it has no chronotropic effect and may cause vasodilation.3,8 HIET is safe, and adverse events are predictable, uncommon, and easily managed.2,8 The maximum safe dose of insulin is unknown, but loading doses of 0.5–1.0 IU/kg followed by infusions of 0.1–2.5 IU/kg/h are typically used.8 Interestingly, neither the inadvertent administration of a 1000 IU insulin loading dose for verapamil toxicity13 nor treatment of toxic cardiogenic shock for 2 days with a 6 IU/kg/h insulin infusion had any adverse effects.14 Adverse effects of HIET include hypoglycaemia, hypokalaemia, hypomagnesaemia, and hypophosphataemia.2,6,8 Although these are rarely clinically significant, they necessitate careful monitoring. Hypoglycaemia (blood glucose < 3.3 mmol/L) occurred in 16% of 55 published cases,8 and no cases of hypoglycaemia within 24 hours of CCB overdose were noted in Greene and colleagues’ series of seven cases.2 Greene et al also reported a mean dextrose requirement of 0.05 g/kg/h (range, 0–0.17 g/kg/h), although the mean blood glucose level exceeded the euglycaemic range.2 Some cases of severe CCB toxicity in patients presenting with hyperglycaemia do not require any additional glucose administration despite high-dose insulin therapy,15 and hypoglycaemia may be more likely in milder cases without marked hypotension.8 In addition, hypokalaemia (potassium < 3.5 mmol/L) was noted in only two patients in Greene et al’s small series, with a minimum potassium level of 2.8 mmol/L.2 Excessive correction of hypokalaemia should be avoided, because it reflects the intracellular shift of potassium from the extracellular compartment due to the action of insulin, rather than a potassium-depleted state.4 Interestingly, hypokalaemia in HIET may augment myocardial contractility by enhancing calcium entry during systole, and increased intracellular potassium may have a membrane-stabilising effect in excitable cells.4,6 In conclusion, we advocate consideration of the early use of HIET (as detailed in Box 2) for the prevention and treatment of life-threatening complications from potentially lethal CCB overdoses. HIET is safe, inexpensive and freely available, and suitable for use even in remote settings before transfer to a referral centre. 1 Early changes in the patient’s systolic blood pressure (SBP) and heart rate, relative to treatment with high-dose insulin and adrenaline infusions Following administration of a 0.5 IU/kg short-acting insulin bolus 3.5 hours after presentation, a short-acting insulin intravenous infusion (0.5 IU/kg/h) was commenced (black line), and the patient’s blood pressure improved. The infusion was abruptly discontinued 2 hours later and the patient again became hypotensive. This resolved following commencement of an adrenaline infusion (20 μg/min) (grey arrow), and the insulin infusion (0.5 IU/kg/h) was restarted 8.5 hours after presentation (black arrow). 2 Recommended high-dose insulin euglycaemic therapy protocol,3,4,9 based on the clinical experience of the Western Australian Toxicology Service, published case reports, reviews and animal studies Commence therapy with: Glucose 25 g (50 mL of 50% solution) IV bolus, unless marked hyperglycaemia (blood glucose > 22 mmol/L) is present Short-acting insulin 1 IU/kg bolus to maximally saturate insulin receptors Continue therapy with: Short-acting insulin infusion starting at 0.5 IU/kg/h and titrated every 30 min to a maximum of 5 IU/kg/h* Dextrose 25 g/h IV infusion titrated to maintain euglycaemia (blood glucose, 5.5–14 mmol/L); central venous access may be required to allow use of concentrated solutions (eg, 50% dextrose) and limit excess volume administration Monitor: Glucose — every 20 min for first hour, then every 1 h Potassium — replace only if < 2.5 mmol/L and there is a source of potassium loss Therapeutic end points: Improvement in myocardial ejection fraction (> 50%); increased BP (systolic BP > 90 mmHg in adults) Adequate heart rate (> 60 beats/min) Resolution of acidaemia; euglycaemia; adequate urine output (1–2 mL/kg/h) Reversal of cardiac conduction abnormalities (QRS interval < 120 ms) Improved mentation Therapy is weaned after the withdrawal of other vasopressors, as cardiotoxicity resolves. Dextrose may be required after cessation of insulin. IV = intravenous. BP = blood pressure. * The maximum safe and effective rate of infusion is unknown but may be even higher than 5 IU/kg/h. In animal studies, insulin infusions as high as 10 IU/kg/h have been safely used.11

Christopher P Nickson MB ChB, DTMH, GCertClinTox · Mark Little FACEM, DTMH, MPHTM

To the Editor: Nordin and colleagues raised important issues about prescribing for osteoporosis.1 We agree that the Pharmaceutical Benefits Schedule guidelines for therapy are imperfect, but they do not necessarily lead, as Nordin et al claim, to inappropriate prescribing. For historical reasons, osteoporosis is held to be synonymous with vertebral fractures, but this misrepresents the epidemiology of fractures. Non-vertebral fractures account for 80% of all fractures and 90% of the loss of quality of life and economic costs. Vertebral fractures contribute only 20% of the burden.2 Most fractures arise in the large population at moderate risk with osteopenia — the “bell” of the Gaussian bone mineral density (BMD) distribution, not its “tail”, which comprises those with osteoporosis (defined by a bone densitometry T-score less than – 2.5). Concentrating on vertebral fractures and screening for osteoporosis with bone densitometry, as recommended by Nordin et al, is no solution to this public health problem. Nutritional change and exercise are appealing because they are safe and cost-effective approaches for early intervention, but are supported only by level D evidence (expert opinion).3 Although these approaches are plausible, no trials demonstrate their antifracture efficacy. There are no means of early identification of individuals who will sustain a fracture. Densitometry is neither sensitive nor specific for fracture; most people with osteoporosis do not sustain a fracture, and most fractures arise in people without osteoporosis, who would, paradoxically, be excluded from treatment by screening.4 Bone densitometry should be more accessible for case finding, but its use for screening does not reduce the fracture burden because of this screening paradox. However, Medicare reimbursement for densitometry is available for high-risk individuals (those with premature menopause, other illnesses or who are taking corticosteroids), not just for those aged over 70 years or those with fractures. Restricting treatment on the basis of BMD results is not advocated by the Australian and New Zealand Bone and Mineral Society precisely because it excludes this moderate-risk group from treatment, particularly those with fractures and osteopenia. There is level A evidence (meta-analysis of multiple randomised trials)5 for the antifracture efficacy of bisphosphonates in patients with osteoporosis, and evidence based on single trials6 of their antifracture efficacy in those with osteopenia and prevalent fractures, whose fracture risk is similar to that of people with osteoporosis and no prevalent fracture. There is limited evidence of antifracture efficacy of bisphosphonates in individuals with osteopenia alone.6 Preventing the first fracture is important, and guidelines are deficient in this way. Case finding to estimate absolute risk is the best approach available at this time, using risk factors, remodelling markers and, more recently, microstructural analysis to improve sensitivity and specificity. Rather than inappropriate or overprescribing, evidence suggests underutilisation of drug therapy for osteoporosis.7,8 Osteoporosis remains underdiagnosed, underinvestigated and undertreated, and limiting access to bone densitometry is not supported by the Australian and New Zealand Bone and Mineral Society.

Ego Seeman · Mark A Kotowicz · Peter T Nash · Philip N Sambrook

In reply: Seeman and colleagues agree that most patients with minimal trauma fractures do not have osteoporosis. The figures are clear: only 13% of patients with a peripheral fracture have a hip bone mineral density (BMD) T-score less than or equal to − 2.5 and only 25% have a score less than or equal to − 1.5. The corresponding figures for vertebral fractures are 25% and 38%, respectively.1 We do not argue that the − 2.5 T-score threshold for defining osteoporosis is sacrosanct, but simply that some bone density threshold be defined for subsidised therapy, for which virtually all the supporting evidence is based on treatment of patients with established osteoporosis. Osteopenia is an artificial concept with an arbitrary definition, but we agree that the T-score threshold for subsidised therapy need not be as low in those with prevalent adult fracture as in those without — perhaps − 1.5, which is the threshold recently adopted for patients receiving corticosteroid therapy. We disagree about the predictive power of bone densitometry; it is comparable to that of blood cholesterol level for heart attacks and blood pressure for stroke.2 It therefore makes sense to measure BMD in all women at menopause and all men at age 60 years to identify those with osteoporosis before they sustain fractures, as well as those with normal but negative T-scores, who have a fracture risk twice that of those with positive T-scores.3 Those with proven osteoporosis could receive subsidised therapy, and those with low normal values could be advised on lifestyle measures, such as calcium supplementation (which significantly delays or prevents bone loss in postmenopausal women).4 People with positive T-scores can be reassured. To suggest that no trials have demonstrated the antifracture efficacy of nutritional measures is to argue against three large meta-analyses showing significant prevention of fractures with vitamin D and calcium supplementation.5-7 The additional cost of confirming low bone density before providing subsidised therapy in fracture cases is likely to be more than offset by the savings from reduced inappropriate therapy; bone densitometry costs about $80 per test, but bisphosphonate therapy costs about $50 a month for each patient. The extra cost of bone densitometry for every woman at menopause and every man at age 60 years could be $20 million a year, but even with subsidised therapy for those without fracture but proven osteoporosis (with a T-score less than or equal to − 2.5, for instance), the cost is also likely to be more than offset in the long term by reducing the enormous cost of osteoporotic fractures ($8 billion annually8). We find it hard to understand why any of our colleagues would not support proposals that would transfer treatment from those who do not need it to those who do.

B E Christopher Nordin · Michael Horowitz

To the Editor: The ASPREE (ASPirin in Reducing Events in the Elderly) study may provide useful data on the benefits and risks of aspirin therapy in patients aged ≥ 70 years, as described by Woods and colleagues.1 However, the decision to allow general practitioner co-investigators to “help decide whether the patient is a suitable candidate for the placebo-controlled trial” introduces a source of selection bias that may limit the generalisability of the results. Without pre-specified objective selection criteria, it is likely that primary-prevention patients assessed by GP co-investigators as being at high vascular risk will be excluded because the GPs believe they should be taking antiplatelet agents. Similarly, those at low risk may be thought inappropriate participants because the risks of random allocation to this therapy might outweigh the perceived benefits, as has been shown in previous meta-analyses.2,3 ASPREE may end up with a disproportionate number of intermediate-risk patients. In the case of diabetes, a recent observational study from our group highlighted patients with diabetes and retinopathy and those taking a sulfonylurea as being at increased risk of complicated peptic ulcer disease.4 By contrast, we did not find that aspirin use, positive serological results for Helicobacter pylori, or the interaction of these two factors predicted complicated peptic ulcer disease. If GP co-investigators were aware of these findings, they might also influence the screening and recruitment of patients with diabetes to ASPREE. According to the trial registration details (ISRCTN83772183), patients with diabetes were eligible for recruitment to ASPREE from late February 2009, even though the trial started 6 years ago.5 Given this delayed eligibility, the fact that a substantial proportion of patients with diabetes older than 70 years will already have vascular disease, and the expected total sample size of 19 000,1 the trial might include fewer than 1000 patients with diabetes and thus have insufficient statistical power to assess the risks and benefits of aspirin for primary prevention in this important subgroup. We question why subjective assessment forms part of patient selection for a potentially important study such as ASPREE, and also what steps the investigators are taking to determine whether the sample they recruit is representative. In addition, details of planned statistical analyses involving diabetic participants in this non-superiority trial would be reassuring.

Timothy M E Davis · Brett A Sillars · Wendy A Davis

In reply: Recruitment to clinical trials through general practice is representative of the population, as a high proportion of all Australians regularly attend their general practitioners.1 GP co-investigators are appropriate to decide whether their patients are suitable for the ASPREE (ASPirin in Reducing Events in the Elderly) study because their assessment includes objective inclusion and exclusion criteria that must be satisfied before enrolment in the study (clinical trial registration number ISRCTN83772183),2 as well as patient-specific potential risks with using aspirin, and known medical factors likely to influence patient survival during the trial. These include the risk of complicated peptic ulcer disease in patients with diabetes treated with a sulfonylurea.3 GP co-investigators support participation in ASPREE by eligible patients because of aspirin’s therapeutic equipoise for primary prevention in older patients4 and in those with diabetes.5 Because of age alone, ASPREE participants will be at least at intermediate risk of cardiovascular disease and also at increased risk of bleeding. Determining the aspirin balance underpins the importance of collecting more data in older people, who have been under-represented in previous primary prevention trials. ASPREE is a superiority trial with pre-specified subgroup analyses, including for the subgroup with diabetes.2 The study is powered to address the primary question reliably in the total cohort rather than subgroups. To date, fewer than 500 participants have been randomly allocated, with recruitment slowed subject to National Institutes of Health funding deliberations. Recruitment will be reinvigorated in late 2009, and will continue to include people with diabetes.

Robyn L Woods · Mark R Nelson · Andrew M Tonkin · Christopher M Reid

To the Editor: Wiseman and colleagues reported the 9-month virological follow-up of babies born to pregnant women attending urban antenatal clinics who tested positive for hepatitis B surface antigen (HBsAg).1 Evaluation of outcomes is vital to determine implementation and effectiveness of current policy. The authors state that hepatitis B immunoglobulin (HBIG) and hepatitis B virus (HBV) vaccine were delivered within 12 hours of birth to all infants of HBsAg-positive mothers. Nine months after birth, transmission was documented in only four infants, all of whom were born to mothers who were positive for hepatitis B “e” antigen (HBeAg) and had very high HBV DNA levels (> 108 copies/mL). Yet one of the four infected infants had inadvertently not received the “routinely offered” HBIG. Whether any other babies (even if not infected) also failed to receive timely active and passive immunisation was not explicitly reported. The other three infected infants completed HBIG injection and HBV vaccination according to the “recommended schedule”. Given that the Australian immunisation handbook states that [t]he first dose of monovalent hepatitis B vaccine should be given at the same time as HBIG ... as soon as possible — preferably within 24 hours of birth, and definitely within 7 days,2 the exact time is unclear. Potentially, a delay of many hours to many days could occur. Yet, for all infectious diseases for which post-exposure prophylaxis is given, administration as soon as possible after exposure is universally recommended to prevent transmission.3 For babies born to known HBeAg-positive mothers, particular effort is warranted to ensure that they receive HBIG and HBV vaccine immediately after delivery, and certainly within hours of birth. There are many difficulties in achieving high rates of follow-up in this group, and only 66% of babies in the study by Wiseman and colleagues had virological follow-up results available. Unfortunately, the authors did not make the important distinction between babies lost to follow-up and those who were not yet 9 months old at the time of follow-up. This is in spite of the fact that the study included many South-East Asian women, who have markers of high HBV replication and whose follow-up is suboptimal.4 Evaluation of HBV vaccination policy requires that studies report fully on outcomes, including loss to follow-up. Also, given that delay in administration of HBIG and HBV vaccine after delivery may be a critical source of variation in outcome, future studies should specifically report this information separately for all births to HBsAg- and HBeAg-positive mothers, and for any cases in which transmission does occur.

Sandra C Thompson

In reply: We thank Thompson for her comments. We endeavoured to contact women by phone, by letter, or through their local doctor (if known). With respect to the 69 infants lost to follow-up, five of the mothers declined assessment, four had moved interstate or overseas with their families, five had infants who had not reached 9 months of age, and the remaining mothers were uncontactable. Follow-up of a cohort of this kind is difficult, for reasons that include language barriers and high rates of mobility. Furthermore, at the time of the study, testing the babies was not standard practice and not enthusiastically received by all mothers. We are not a public health unit and are not resourced to pursue follow-up beyond the measures described. Nevertheless, through strong engagement with the mothers, who were referred on the basis of their hepatitis B virus (HBV) infection, we achieved follow-up for a large number of babies. The data stand as valuable but not perfect. As mentioned in our article,1 vaccination practice for babies born to infected mothers is for hepatitis B immunoglobulin and the first HBV vaccine dose to be given (in opposite thighs) within 12 hours of birth. The babies’ vaccination records were checked by consulting the “blue book”, a standardised medical record for infants, and, for those infected, by cross-checking with the hospital medication chart.

Miriam T Levy · Elke Wiseman

To the Editor: I was interested to read the results of Sweidan and colleagues’ study of drug interaction alerts in prescribing and dispensing software.1 I believe their use of the terms “sensitivity” and “specificity” differ from the standard definitions, which are usually: Sensitivity = true positives ÷ (true positives + false negatives) Specificity = true negatives ÷ (true negatives + false positives)2 To test sensitivity and specificity, one requires a dataset that includes positives and negatives. I do not view “minor interactions” as a complete set of negatives, because a complete set of negatives should include a statistically valid number of randomly chosen drug sets without interactions. Minor interactions do not meet my criteria for “negatives” because, to me, a minor interaction is still an interaction that may sometimes be clinically significant. A true negative should meet the test of “never clinically significant”. Some reported minor interactions would meet that test and some would not. I believe sensitivity and specificity data should be reported for both major and minor interaction alerts. I also believe there should be some alignment of definitions between “drug interaction” research and “adverse drug event” research.3 Bates and colleagues talked about “adverse drug events” and “preventable adverse drug events” in 1995.4 Of most clinical interest are the preventable adverse drug events, which could be minimised by the use of appropriate decision support.5,6 Certainly, there is a need for independent assessment of the quality of electronic prescribing decision support systems. A robust assessment methodology is required to permit potential government regulation of such resources, which are of national and community importance.

Ian R Cheong

To the Editor: As the former Clinical Information Specialist Manager for the MIMS DrugAlert knowledgebase (from 2003 to 2005), I write in response to the study by Sweidan and colleagues examining the quality of drug interaction alerts in prescribing and dispensing software.1 The authors point out that the success of any knowledgebase in providing clear, correct and specific alerts at the point of care is subject to the quality of its technical integration into decision support software. I would like to add that the sensitivity of drug interaction decision support is determined largely by the knowledgebase, while the specificity of the system is subject to the intelligence of the software in which it is employed. I would be interested to know if the low specificity that Sweidan et al found for the MIMS DrugAlert database was due to lack of use of the severity or level of evidence settings, or having these set at inappropriate levels. The MIMS DrugAlert knowledgebase was in some ways a unique decision support database, written by Australian staff for use in Australia and New Zealand. It soon became one of the largest commercially available databases of drug interaction information in the world, covering over 4600 drug-class and individual drug interactions. Its writing alone was a remarkable feat, being completed in a matter of months and further expanded over a subsequent 18-month period. There are significant variations in practical advice between American and European sources of drug interaction information. In writing the MIMS DrugAlert database, we sought to communicate “the right information, at the right time, in the right way” to local professionals. The foundations of MIMS DrugAlert were based on a clear understanding that we would be representing relatively simple pharmacological principles through the structure and content of a relational database. This meant creating interacting drug classes reflective of the pharmacological properties of groups of drugs, rather than simply grouping drugs based on their chemical families alone. Sweidan and colleagues should be congratulated on highlighting the need for comprehensive, accurate and useful information that can reduce medication error and save lives at the point of care. What is lacking is a clinical outcomes-based study focusing on the real-world benefits that can be achieved if the right system can be implemented in the right way, at the right price. Perhaps this type of research would then build on the excellent, basic foundational research carried out by Sweidan et al.

Bryan W Tan

In reply: Cheong notes that the terms “sensitivity” and “specificity” have a slightly different meaning in our study compared with the usual definitions. This was intentional, and the definitions we used are clearly described in our article.1 Our definitions for sensitivity and specificity were based on two important practical considerations. First, an electronic prescribing system should alert the clinician to potentially clinically significant drug interactions (“true positives” by our definition); and second, a system should not inundate clinicians with alerts containing irrelevant or unhelpful information about minor or clinically unimportant interactions (“false positives” by our definition). We know that these latter alerts can cause “alert fatigue” and are a subject of complaint for doctors and pharmacists. We are not aware of there being any problem with prescribing systems producing alerts for pairs of drugs that do not interact at all; hence, we did not investigate this group. Tan questions whether the low specificity we found for the MIMS DrugAlert database may have been due to inappropriate severity level settings. Although it might seem appealing to reduce the number of alerts by allowing users to “switch off” drug interaction alerts that are classified as low severity, there are difficulties in doing this because of a lack of evidence for the application of severity ratings to drug interactions. Severity ratings are subjective — studies have shown there is little consensus on such ratings between major reference sources.2,3 This is not surprising, given that there is little evidence available on adverse clinical outcomes resulting from drug interactions, and also because the clinical outcome is context-dependent according to variables such as patient characteristics and drug dosage. We believe that, rather than relying on software vendors or users to switch off some alerts, drug interaction knowledgebases should include only potentially clinically significant interactions. We tested all systems at the lowest severity setting (if available) for consistency, and to maximise detection of drug interaction alerts. For minor interactions, the rating was based on both presence of the alert and quality of the information — if a minor interaction was either not detected or was detected and provided appropriate information indicating it was minor, then it was a “pass”.

Michelle Sweidan · James F Reeve · Jo-anne E Brien · Pradeep Jayasuriya · Jennifer H Martin · Graeme M Vernon

To the Editor: Francis and colleagues revealed a significant 29-minute decrease in the median emergency department (ED) length of stay and reductions in mean turnaround times for full blood count requests following the redesign of pathology processes.1 Laboratory performance and clinician satisfaction are intrinsically bound up with the timeliness of test results, not least because of their effects on patient diagnosis and treatment. The association between test turnaround times and ED length of stay is difficult to decipher. The reasons for this, as pointed out by Francis et al, include the many potential variables that contribute to patient length of stay in EDs. Turnaround times can also vary dramatically according to laboratory operating procedures and work processes. Nevertheless, there is a strong imperative to monitor these indicators as contributors to designing effective interventions to improve the quality and outcomes of patient care. Our research has also revealed that pathology test turnaround times are a significant contributor to ED length of stay at a major teaching hospital in Sydney. Using regression analysis to account for a number of contributing length-of-stay variables (eg, triage category, patient age, number of tests ordered), we produced a model that accounted for 25.4% of the variance in ED length of stay, of which pathology test turnaround time was a significant contributor.2 Further, studies of the effects of electronic test-ordering systems on test turnaround times in five Australian hospitals have shown that introduction of these systems in each instance was associated with significant declines in test turnaround times.2-4 Thus, there appears to be converging evidence of a relationship between efficient test ordering and processing and reduced ED length of stay.5 In addition to the types of interventions described by Francis et al, electronic test ordering should be considered as a system-wide intervention that may contribute to improved efficiency and patient outcomes. Decision support within such systems provides an added ability to provide alerts and guidance in the test-ordering process.

Andrew Georgiou · Johanna I Westbrook

In reply: A recent report on the state of Australian public hospitals highlights figures of 320.6 emergency presentations per 1000 weighted population, with 88% of presentations being triage categories 1–4, and 66% of patients not admitted.1 In our experience, pathology tests are performed on more than 50% of patients in these triage categories who present to emergency departments, and decisions regarding patient care are delayed pending availability of test results. In addition to the initiatives that we described,2 Georgiou and Westbrook describe other initiatives that deliver significant, sustained improvements in health care efficiency. Many have emphasised the need to improve efficiency in the health care system by utilising evidence-based best practice. However, a recently published discussion paper highlights the challenges associated with ensuring that health care workers have access to, and actually use, evidence-based processes and protocols that have been shown to benefit patients.3 Similarly, delays in care may contribute to patient harm, and decisions about resource allocation and organisational systems do not always explicitly take this risk into consideration.3 These challenges may be partly related to the different funding arrangements in the Australian health care system. Apart from the obvious federal–state dichotomy, diagnostics, such as pathology services, and the associated information technology are often funded separately to the hospitals and health care professionals relying on these services. As a result, one of the challenges of implementing initiatives that improve efficiency relates to current and historical allocative funding arrangements, where costs may be borne by one cost centre, and benefits are delivered to patients and other elements of the health care system (ie, other health care providers and departments). It is essential that the Productivity Commission4 considers all of these elements in its review to identify significant efficiency improvements within the hospital system. Effectiveness, allocative efficiency and dynamic efficiency are just as important as simple economic efficiency. Unnecessary delays in the health care system are not only associated with capital costs — they are also associated with an array of direct and indirect costs related to caring for patients who endure an unnecessarily protracted journey through the health care system. It will take courage and commitment to implement and achieve appropriate use of evidence-based care (perhaps via mandates3) and appropriately fund all elements of patient care, so that improvements in care and overall cost savings are not hindered by historical funding constraints.

Andrew J Francis · Michael J Ray · Mary C Marshall

Australian autism handbook. The essential resource guide for autism spectrum disorders. Benison O’Reilly, Seana Smith. Sydney: Jane Curry Publishing, 2008 (xv + 399 pp). ISBN 978 0 9804758 1 4. Autism is not as rare as we once thought. Recent Australian research indicates autism occurs in one child in 160, and half a million Australians are living in a family that has a child or adult with autism. The annual cost of autism spectrum disorders (ASDs) to the community is estimated at between $4.5 and $7 billion. It is an expensive disability for both the government and for families. For example, the cost of intensive applied behavioural analysis for a family is around $40 000 per annum, with a program in the preschool years lasting 2 to 4 years. While most of the literature on autism, especially for parents, is published in the United States or the United Kingdom and refers to American or British services, we now at last have an Australian guidebook for families. The authors are parents of children with ASD, and the book is primarily written for families of a newly diagnosed child. However, the Australian autism handbook will be invaluable for clinicians as a resource when talking to families and providing advice on services and resources. The text often refers to Australian research, and we need to recognise the degree and depth of Australian expertise and research on ASD. This book provides current information on services in each state or territory, the latest Medicare initiatives, and research areas of Australian specialists and academics. Clinicians will be interested in the perspectives and experiences of families (such as the susceptibility of parents of a child with autism to develop signs of depression), and to learn more about the latest treatments that parents have heard about and may request for their son or daughter with autism.

Tony Attwood

Itchy eyes, itchy nose If your patients suffer from allergic conjunctivitis but don’t respond well to local treatment, it might be worth checking to see if they have allergic rhinitis, say Dutch researchers. The study aimed to investigate the role of nasal allergy in seasonal and perennial allergic conjunctivitis, and involved 61 adult patients with allergic conjunctivitis who responded poorly to local treatment. The patients were subjected to nasal challenges with allergens, and the nasal and ocular responses measured. A significant number developed a conjunctival response as well as a nasal reaction to the allergens. The authors comment that there may be two types of allergic conjunctivitis: a primary form with the initial reaction in the conjunctiva, and a secondary type induced by an allergic reaction occurring initially in the nasal mucosa, but with clinical symptoms displayed in the conjunctiva. They suggest performing nasal provocation tests in combination with monitoring the cornea in patients who appear refractory to conventional ophthalmological treatment. Clin Experiment Ophthalmol 2009; 37: 448-457 Mother’s BMI a weighty issue for baby There appears to be an association between the body mass index (BMI) of a woman before she becomes pregnant (pBMI) and the weight of her infant at 14 months, according to the results of a large cohort study. Researchers in the Netherlands collected data on BMI prior to pregnancy from over 3000 women and recorded the weight of their babies at 14 months of age. Univariate analysis showed a strong positive association between pBMI and weight of the child at 14 months, with one unit increase in pBMI associated with an increase of 29 g in weight of the child. Other factors associated with weight at 14 months included birthweight, gestational age, sex, maternal age, and ethnicity. The association with pBMI remained significant after adjustment for possible confounding variables: birthweight was apparently responsible for 10 g (1/3) of the pBMI effect. The authors suggest that unknown intrauterine factors not related to birthweight may affect the infant’s weight later in life. Arch Dis Child 2009; 94: 587-595 Talking about surgery Doctors and patients may not be on the same page when discussing the risks and outcomes of complex surgery, say Norwegian researchers. In a qualitative study of doctor-patient dialogues before high-risk cardiac procedures, the conversations were analysed to reveal important aspects of the decision-making process. While patients focussed on uncertainty about survival and trusting the doctor’s proficiency, doctors tended to respond to uncertainty by imparting complex information about risk, warnings and recommendations. The authors conclude that, despite the uneven power relations in such a dialogue, most patients showed profound confidence and unconditional trust in their doctor. Heart 2009; 95: 1245-1249 Aspirin and colon cancer There is substantial evidence from randomised trials that regular intake of aspirin reduces the risk of colorectal cancer, but little is known about the effect of aspirin on survival in patients with these malignancies. Aspirin inhibits cyclooxygenase 2 (COX-2), which is over-expressed in most human colorectal neoplasias. US researchers have conducted a large, long-term, prospective cohort study involving over 1200 participants with colorectal cancer to assess the impact of aspirin on colorectal cancer-specific and overall mortality. Patients were followed up for a median of 11.8 years, during which researchers observed a lower risk of death from colorectal cancer and lower overall mortality in those who used aspirin regularly. In addition, immunohistochemical assessment was performed on the cancers from 459 patients to determine tumour expression of COX-2. Researchers found that regular aspirin use after diagnosis was particularly associated with reduced mortality in patients whose tumours overexpressed COX-2. The authors comment that, although these findings are biologically plausible and have promise for treatment, further studies including placebo-controlled trials are necessary to determine the benefits versus the risks of aspirin use in this setting. JAMA 2009; 302: 649-659

Tanya Grassi