Cardiovascular diseases

In reply: My article1 was submitted for debate when two separate, industry-sponsored cholesterol awareness campaigns were simultaneously targeting the Australian public. There is potential for public confusion following exposure to concurrent campaigns with differing sponsors, creative techniques, and messages such as “Test the Nation”. My article did not diminish the importance of cholesterol screening (nor of the prevention of or treatment for hyperlipidaemia), and indeed it reiterated the National Heart Foundation guidelines. Its intent was to raise debate about industry-sponsored disease awareness campaigns, as there is growing concern in Australia about “disease mongering”2 and the evidence that this is occurring in the cholesterol market in the United States.3 I agree with Sullivan that the Australian public needs education about asymptomatic risk factors, including hypertension and hyperlipidaemia. Ideally, this would include clear information and non-emotive marketing techniques to convey who is most at risk, as well as transparent disclosure of sponsor interests.4 Contrary to Sullivan’s charge, I believe there are many opportunities for quality health education and behaviour change programs, several of which the Centre for Health Initiatives is currently undertaking.5 The intent of my article was to generate critical analysis of industry-sponsored campaigns in order to improve their public health benefit.

Danika V Hall

Objective: To assess the performance of the Framingham and United Kingdom Prospective Diabetes Study (UKPDS) cardiovascular risk equations in Australian patients with type 2 diabetes who were initially free of cardiovascular disease (CVD).Design and setting: The Fremantle Diabetes Study (FDS), a community-based longitudinal observational study; data for the period 1993–2006 were used.Patients: Of the 815 FDS participants with type 2 diabetes who were initially CVD-free, 791 (97%) were eligible for assessment using the UKPDS equations, and 697 (86%) using the Framingham equation.Main outcome measures: CVD endpoints during 5 years of follow-up. For the UKPDS equations, these were fatal myocardial infarction (MI) or sudden death (fatal coronary heart disease [CHD]); hospitalisation for/with or death from MI or sudden death (all CHD); fatal stroke; and all stroke. For the Framingham equation, they were all MI, sudden death or angina pectoris (CHD).Results: During follow-up to first CVD event, death or 5 years, there were 38 MIs (11 fatal) and 23 strokes (13 fatal) in the UKPDS-assessable cohort of FDS participants. The UKPDS risk equations for all CHD, fatal CHD, and all stroke overestimated the number of events by 6.5, 2.8 and 1.8 times, respectively. The risk equation for fatal stroke underestimated the number of events by 38%. The UKPDS CHD risk equations showed modest discrimination and poor calibration, while the stroke risk equations showed good discrimination and calibration. The Framingham equation predicted 28% fewer CHD events than occurred (93 v 130), and discrimination and calibration were poor.Conclusions: While the UKPDS stroke risk equations performed relatively well, the UKPDS and Framingham CHD risk equations are not suitable for predicting risk in Australians with type 2 diabetes.

Wendy A Davis MPH, PhD · Stephen Colagiuri FRACP · Timothy M E Davis DPhil, FRACP

Clozapine is a valuable drug for patients with treatment-resistant schizophrenia. Myocarditis is the most publicised cardiac complication of clozapine treatment, but cardiomyopathy and pericarditis have also been reported. Myocarditis has heterogeneous and non-specific presenting features, making it difficult to identify patients with clozapine-related myocarditis clinically. A high index of suspicion is required. The gold standard for diagnosis of myocarditis is an endomyocardial biopsy, but this is not a practical initial approach. Transthoracic echocardiography is a valuable, reproducible and widely available tool to assist in diagnosis of clozapine-induced cardiotoxicity. The level of B-type natriuretic peptide, a hormone secreted in response to ventricular wall stress, may be useful for evaluating patients with clozapine-induced cardiac dysfunction and may in the future be useful for screening asymptomatic patients. The mainstay of treatment of clozapine-induced cardiotoxicity is cessation of clozapine and provision of supportive care.

Jamie J Layland MB ChB, MRCP(UK) · Danny Liew MB BS(Hons), FRACP, PhD · David L Prior MB BS, FRACP, PhD

Patients with schizophrenia have a wide range of risk factors for cardiometabolic disease, at rates 1.5–5 times greater than the general population. Despite the provision of many sets of guidelines and protocols for screening and monitoring of cardiometabolic risks, morbidity and mortality rates for those with psychotic illnesses remain excessive and premature. Surveys of mental health practitioners reveal a clear acknowledgement of the importance of managing cardiometabolic risks and subsequent comorbidity. However, inadequate screening rates of patients with antipsychotic-treated mental illnesses suggest “knowing is not doing”. Surmountable barriers (at service, patient and illness levels) to adequate integrated health care are not being adequately challenged for this population. Recommendations to improve the situation include service reorganisation, communication enhancement, improved training and education, better incentives, accreditation rigour, and government leadership.

Tim J R Lambert MB BS, PhD, FRANZCP · John W Newcomer MD

To the Editor: A 56-year-old woman was recently admitted with recurrent large-volume haemoptysis associated with left-sided tearing thoracic pain. Growing up on a sheep farm in rural New South Wales, she had been diagnosed at age 8 years with pulmonary hydatidosis, which remained dormant on periodic clinical assessments. However, 2 years before presentation she started to cough up gelatinous material containing scolices of Echinococcus granulosus. Surgery was declined at that time due to the anticipated complexity of the operation and associated high perioperative risk. Long-term anthelmintic therapy was commenced. On admission, a computed tomography (CT) scan showed a contained aortic pseudoaneurysm (Box), consistent with rupture of the aorta into the hydatid cyst. Other images showed the cyst containing gas, indicating communication with the airway. After stabilisation, the patient was transferred to a cardiothoracic centre. A left upper lobectomy with dissection and removal of the mediastinal cyst was undertaken through a median sternotomy, and the aortic fistula was successfully repaired using bovine pericardial strips. Intraoperatively, there was no evidence of pericardial involvement. Histopathological examination showed a disrupted and degenerate hydatid cyst without a germinal layer and no protoscolices. The patient received albendazole for 6 months after surgery and her recovery was uneventful. Hydatid disease is caused by the intestinal parasitic tapeworm E. granulosus which, in Australia, is most prevalent in the eastern half of NSW at higher altitudes.1 Symptomatic intramural aortic-wall hydatidosis causing aortic-wall rupture and pseudoaneurysm formation has been described in fewer than a dozen cases.2 Hypotheses for arterial-wall invasion include dissemination during cardiac surgery; entry through vasa vasorum or pre-existing small intimal tears or aneurysms; or partial incorporation of the aortic wall into the hydatid pericyst.2,3 We identified four case reports in adults describing fistula formation between a pulmonary hydatid cyst and the aorta, including three European cases3-5 and one South African case (published twice).6,7 All patients were middle-aged men: two presented with chest pain and large-volume haemoptysis, one with anaphylactic shock and bilateral ischaemic lower limbs from aortic-wall hydatid cyst emboli, and one with a cyst eroding the abdominal aorta (found incidentally during surgery for a coeliac trunk aneurysm). One patient died during removal and another patient after removal of the primary cyst. Haemoptysis in pulmonary hydatid disease is a common presenting symptom. Mechanisms include pressure erosion of a bronchus, obstructive infection, cyst rupture or — very rarely, and emphasised in our case — erosion of a major vascular structure. Aortobronchial fistula resulting from pulmonary hydatidosis A: Contrast-enhanced thoracic computed tomography scan showing consolidation and cavitation within the left upper lobe. A multiloculated 4 cm diameter peripherally calcified hydatid cyst was present in the medial aspect of the left upper lobe (white arrows), penetrating under the aortopulmonary window. Contrast medium extended posteriorly into the base of the lesion, suggestive of an aortic leak (black arrow). B: Coronal reconstruction of the aortic arch demonstrated a round collection of contrast medium with a 1.4 cm base (black arrow), consistent with a contained saccular aortic pseudoaneurysm.

Stefan Buchholz · David Sowden · Troy Stapleton · Peter Pohlner · Craig Wright

Australia needs to develop its own guidelines based on local data New guidelines for testing and treating lipid abnormalities in children have recently been published by the American Academy of Pediatrics and the American Heart Association (Box).1,2 These recommendations, made partly in response to the high prevalence of obesity in children in the United States, provoke consideration of whether they should also be adopted in Australia. The previous US recommendations,3 which targeted cholesterol testing to children with a family history of premature cardiovascular disease or high cholesterol levels, had focused on a population-based approach to treatment through a fat- and cholesterol-restricted diet. Drug therapy was reserved for children with more persistent and extreme elevations in cholesterol level. In contrast, the recent guidelines recommend that testing be broadened to include all overweight or obese children, with the first cholesterol assessment to be done between the ages of 2 and 10 years. The new guidelines further recommend that initiation of drug therapy be considered at a younger age (from 8 years) and with a lower low-density lipoprotein cholesterol (LDL-C) level target for children with multiple cardiovascular risk factors. Indirect evidence suggests that childhood lipid abnormalities are important in the development of cardiovascular disease in adults. For example, autopsy studies indicate that atherosclerosis begins in the young and that the extent of lesions correlates with traditional cardiovascular risk factors, including lipid levels.4 However, advanced atherosclerosis rarely occurs in children and adolescents. Arterial wall thickness in adults, as assessed by carotid artery ultrasonography, is associated with childhood lipid levels, and children with lipid abnormalities display altered arterial structure and function.5,6 However, direct evidence for an association between childhood lipid levels and adult cardiovascular outcomes, such as myocardial infarction and stroke, is not available. Why, then, test children and adolescents at all? Would it be equally effective to test young adults? One important potential rationale for cholesterol testing in children is that lipoprotein levels tend to track from childhood into adult life.7,8 Detection of lipid abnormalities in young children could prompt changes in diet and physical activity that would be required through the whole of life. It is important to note, however, that both universal and targeted lipid testing in children result in a high false-positive rate for adult dyslipidaemia.8,9 Moreover, the predictive value of childhood lipid levels depends on the threshold values used to define dyslipidaemia. Threshold values derived from populations of US children may not be sensitive to trends in childhood lipid levels and overweight and obesity in Australia. The prevalence of childhood overweight and obesity is high and increasing in both Australia and the US.10,11 Moreover, in both countries, lipid abnormalities are common in overweight and obese children,12,13 with low high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels particularly prevalent. Importantly, targeting overweight and obese children for LDL-C testing does not improve the specificity for detecting elevated LDL-C levels in adults.8 Although most overweight and obese children with low HDL-C levels become adults with low HDL-C levels, targeting overweight and obese children for HDL-C testing will not identify the majority of adults with low HDL-C levels.8 Overweight and obese children, whether or not they have high triglyceride and low HDL-C levels, require weight management through changes in diet and physical activity levels. But it is uncertain, particularly in the case of young children, whether knowledge of their lipid status will lead to greater motivation to implement such changes. Improved diet and increased physical activity are both safe and effective ways of reducing cardiovascular risk factors in children, and should be promoted across the whole paediatric population.14-17 Most overweight and obese children could be encouraged to adopt these lifestyle changes without testing their lipid status. Testing for lipid abnormalities could be reserved for older, obese children (> 10 years of age) in the context of an overall assessment of their risk for future cardiovascular disease. Screening based on family history may be hampered by inaccurate or incomplete information and the need for adult family members to have their cholesterol levels measured. However, obtaining an accurate family history, combined with testing of adults to detect those with significant elevation in LDL-C levels, may help identify children with inherited dyslipidaemias (eg, familial hypercholesterolaemia). Such children have the highest risk of premature cardiovascular disease and may benefit most from drug therapy at a young age. The new US recommendations also raise questions about which children should be considered for drug therapy for lipid abnormalities. A number of randomised clinical trials have demonstrated the short-term safety and efficacy of HMG-CoA reductase inhibitors (statins) in children.18 Statins are currently the first-line drug treatment for elevated cholesterol levels in children. However, there is a lack of evidence for their long-term safety, and animal studies have shown they may be toxic to the developing fetus.19 Although there have been no controlled epidemiological studies relating gestational exposure to statins with adverse human pregnancy outcomes, case reports of structural anomalies and the biological plausibility of a teratogenic effect mean that statins are contraindicated in pregnancy.20 Thus, a case can be made for reserving statin therapy for older children at high risk of future cardiovascular disease. In girls, it may be appropriate to delay statin therapy until an age when discussions about reproduction and contraception can occur. A strong family history of premature cardiovascular disease or a rapid progression in surrogate measures of atherosclerosis (eg, carotid arterial wall thickness, measured by ultrasound) may lower the age threshold for statin therapy. In Australia, we should be taking action to address the increasing prevalence of childhood cardiovascular risk factors. However, guidelines from the US may not be appropriate for Australian children, and it is imperative that we formulate new local recommendations based on recent local data. Guidelines for lipid assessment and management in Australia should also propose strategies for reducing cardiovascular risk factors in childhood more generally. This will require discussion and collaboration between clinicians, researchers, and governmental and non-governmental organisations, such as Diabetes Australia, the National Heart Foundation, the Paediatric Cardiac Council of the Cardiac Society of Australia and New Zealand, and the Royal Australasian College of Physicians. In the interim, a careful assessment of the risk of future cardiovascular disease is required for all paediatric patients. This will be based on ascertainment of an accurate family history of premature cardiovascular disease, information on diet and physical activity, anthropometric and blood pressure measurements made at routine paediatric health checks, and the targeted assessment of blood lipid levels in older children with a family history of premature cardiovascular disease or hyperlipidaemia and/or multiple other cardiovascular risk factors, including obesity. Summary of recent changes to recommendations in the United States for cholesterol testing and treatment in children1,2 Stronger recommendations for cholesterol testing in children who have cardiovascular risk factors other than lipid abnormalities — particularly overweight and obesity, but also hypertension, cigarette smoking or diabetes. A stronger recommendation on the timing of initial cholesterol testing: between the ages of 2 and 10 years. A recommendation to consider commencing drug therapy in children aged over 8 years (rather than 10 years), with a target low-density lipoprotein cholesterol level of < 3.3 mmol/L (rather than < 4.1 mmol/L).

Julian G Ayer BSc(Med), MB BS, FRACP · David R Sullivan MB BS, FRACP, FRCPA · Gary F Sholler MB BS, FRACP

Objectives: To determine the incidence and clinical features of acute rheumatic fever (ARF) in Fiji, and the clinical features of patients presenting to hospital in Fiji with rheumatic heart disease (RHD).Design and setting: A prospective surveillance study at the Colonial War Memorial Hospital in Suva over a 23-month period from December 2005 to November 2007.Main outcome measures: Incidence of ARF; clinical features of ARF and RHD.Results: The average annualised incidence of definite cases of ARF in children aged 5–15 years was 15.2 per 100 000 (95% CI, 9.0–22.6). The clinical features of ARF were similar to those in classic descriptions. Carditis was very common, occurring in 79% of cases. There were 103 admissions for RHD in which detailed information was collected, with the most common reason for admission being cardiac failure (51%). The median age at admission with RHD was 26.8 years, and there were 10 deaths of patients with RHD (case fatality rate, 9.7%).Conclusions: Although apparently declining in incidence since the middle of the 20th century, ARF remains a significant health problem in Fiji. RHD affects young people, leading to premature morbidity and mortality. There is an urgent need for effective control of ARF and RHD in Fiji.

Andrew C Steer MB BS, BMedSci, FRACP · Joseph Kado MB BS · Adam W J Jenney MB BS, PhD, FRACP · Michael Batzloff BSc, PhD · Lepani Waqatakirewa MB BS · E Kim Mulholland MB BS, FRACP, MD · Jonathan R Carapetis MB BS, FRACP, PhD

To the Editor: Cardiac rehabilitation (CR) is an underutilised evidence-based treatment.1 Between 1 March 1998 and 28 February 1999, we surveyed 1933 patients aged 20 to 85 years discharged from public hospitals in the Hunter region with principal discharge diagnoses of acute myocardial infarction, unstable angina pectoris, congestive heart failure, and ischaemic heart disease. Patients undergoing coronary artery bypass graft surgery and percutaneous coronary intervention were also included. Among the 1202 respondents (62%), 493 (41%) reported being referred to CR, 309 (26%) reported attending at least one session, and 233 (19%) reported completing all or all but one session.2 The factors associated with referral were younger age, previous participation in CR, admission to a hospital providing CR, a discharge diagnosis of acute myocardial infarction, and coronary artery bypass surgery.3 We provide the following data, pertaining to non-referred patients, within the context of recent government initiatives to improve access to evidence-based treatments. Fifty-seven per cent of respondents (688) had not been referred to CR (2% did not answer this question), 645 of whom had not attended previously. The median age of these 645 people was 70 years. Most were male (64%), married (62%), had not completed high school (54%), were not in full-time employment (81%), had not been admitted to a hospital that offers CR (55%), did not have a discharge diagnosis of acute myocardial infarction (78%), and had not undergone revascularisation (92%). These 645 patients were asked if they thought they would have benefited from attendance at an outpatient CR program. Of the 380 patients who did not think they would have benefited, 41% (157) reported having at least three coronary risk factors, 39% (150) were interested in further services, and 26% (100) reported participating in at least one risk-factor-specific secondary-prevention program (Box 1). In conclusion, many patients who are not referred for CR reported having multiple coronary risk factors, yet few felt they would have benefited from attending CR or had participated in any alternative risk-factor-specific programs. We agree that system factors resulting in failure to refer should be investigated and rectified,1 but our data suggest that many non-referred patients would not attend if invited. This highlights the importance of research testing the efficacy of alternative models of CR in the Australian setting,4,5 and the need for research assessing the effectiveness of these programs in routine health services delivery. 1 Coronary risk factors, and opinions on the need for and participation in risk-factor-specific secondary-prevention programs Felt cardiac rehabilitation would have been beneficial* Total Yes No Number of patients 645 143 (22%) 380 (59%) Number of self-reported coronary risk factors None 60 (9%) 8 (6%) 37 (10%) One 137 (21%) 32 (22%) 73 (19%) Two 180 (28%) 45 (31%) 108 (28%) Three or more 254 (39%) 55 (38%) 157 (41%) Felt the need for further services 321 (50%) 119 (83%) 150 (39%) Chose one or more of the following options: Information on how to prevent or manage further heart trouble 280 (43%) 112 (78%) 124 (33%) Help with how to cope with emotional issues arising from heart problems 169 (26%) 82 (57%) 61 (16%) Exercise classes 130 (20%) 76 (53%) 34 (9%) Nutrition classes 124 (19%) 71 (50%) 34 (9%) Quit-smoking programs 51 (8%) 21 (15%) 21 (6%) Help with stress management 142 (22%) 69 (48%) 51 (13%) Help with getting back to work 35 (5%) 25 (17%) 10 (3%) Undertook risk-factor-specific secondary prevention 187 (29%) 50 (35%) 100 (26%) Participated in the following programs: Home exercise plan provided by hospital 62 (10%) 15 (10%) 34 (9%) Other home-based exercise program 55 (9%) 10 (7%) 31 (8%) Fitness-centre program 7 (1%) 2 (1%) 2 (0.5%) Diet/nutrition program provided by hospital 85 (13%) 27 (19%) 46 (12%) Other diet/nutrition program 57 (9%) 14 (10%) 27 (7%) Quit-smoking program 25 (4%) 7 (5%) 15 (4%) * 19% of non-referred respondents (122/645) did not answer this question.

Natalie A Johnson · Kerry J Inder · Amanda L Nagle · John H Wiggers

To the Editor: The work presented by Chew and colleagues in setting up and using the Acute Coronary Syndrome Prospective Audit (ACACIA) is an important and influential initiative.1 It has the potential to provide a strong evidence base for the design and delivery of cardiac services in Australia. Their article and the accompanying editorial by Scott2 highlighted the difficulty in determining treatment benefit from uncontrolled observational studies. Among the unreported and possibly significant confounders underpinning the association between acute invasive care and the 47% improved 12-month survival in patients treated for acute coronary syndrome is participation in post-event secondary-prevention cardiac rehabilitation. A contemporary systematic review of randomised controlled trials of cardiac rehabilitation reported a significant relative risk reduction in all-cause mortality of 20% (95% CI, 7%–32%) over a median follow-up of 12 months.3 Despite this evidence and the long-term policy of the World Health Organization that cardiac rehabilitation should be available to all patients with cardiovascular disease,4 this secondary-prevention intervention is largely underused, and those who do attend are generally at lower risk of recurrent coronary events than those who do not.5 Further, secondary-prevention cardiac-rehabilitation programs are cost-effective relative to other coronary interventions6 and, along with proven cardioprotective pharmacotherapy and acute invasive care, should be given priority as part of an optimal treatment and management strategy for secondary prevention. The completion of cardiac rehabilitation or other forms of secondary prevention by ACACIA patients may have favourably impacted upon the marked improvement in 12-month survival seen in the ACACIA cohort. Chew and colleagues identified the fact that patients who underwent invasive therapies were also more likely to be treated according to best-practice guidelines.1 It may be that this same group were also more likely to be referred to cardiac-rehabilitation and secondary-prevention programs. It would be of great interest to know if attendance in cardiac-rehabilitation and secondary-prevention programs was recorded in the ACACIA registry and, if so, why those results were not incorporated.

Leigh D Kinsman · Julie Redfern · Tom G Briffa

In reply: It is often hoped that clinical studies can be “all things to all people”. Yet, in reality, clinical registries are optimally designed to answer a limited number of questions such as use of therapies, current treatment, and reassurance (but not proof) of treatment effectiveness. We decided not to collect data on referral to cardiac rehabilitation in our registry.1 In arriving at this decision, we were cognisant of the fact that, important to exploring the benefits or confounding effects of therapies is the ability to define the intervention accurately, and then adjust for the baseline differences between patients receiving and not receiving such treatment. This is problematic when considering “referral to cardiac rehabilitation”. How should cardiac rehabilitation (inhospital, outpatient, single-day, multi-day programs) be defined? Should one assess referral or attendance (partial or complete)? While the value of rehabilitation is well appreciated, it was not the focus of our study. We are designing future observational studies in this area with more focus on the later phase of patients’ admissions and their posthospital management, including rehabilitation. As we cautioned, the magnitude of benefit associated with invasive management in our study should not be overinterpreted. At best, these studies contribute to the totality of evidence, and offer insights into those patients not currently receiving the benefits of our rich evidence base.

Derek P Chew · John V Amerena · Steve G Coverdale · Jamie M Rankin · Carolyn M Astley · Ashish Soman · David B Brieger

To the Editor: Scott was correct in his recent article to emphasise the need for an Australian registry for percutaneous coronary interventions (PCIs).1 To that end, we report an initiative developed by a voluntary collaborative group of interventional cardiologists in Victoria — the Melbourne Interventional Group (MIG) — which has provided a significant volume of contemporary data on the efficacy and safety of PCI.2 Since July 2004, data on over 9500 coronary interventional procedures in over 7500 patients have been collected into this registry, using data elements and methods based on those of the United States National Cardiac Disease Registry and the Victorian Cardiothoracic Surgical Database.3,4 Methods for data collection and analysis, and the format of data forms have been published.5 The data elements, developed by an MIG working group, have been peer reviewed and are currently under review for publication. MIG has a formal governance structure with a constitution, steering committee and subcommittees that govern data quality, database development, research, publication and funding. Approval for the conduct of the registry has been obtained from the ethics committees of all participating hospitals; all patients enrolled provide informed consent for initial and long-term data collection in a manner similar to that used for the Victorian Cardiothoracic Surgical Database.3 Results from MIG to date show that PCI practice differs between Australia and the US, and that use of drug-eluting stents (DES) is safe and effective in reducing restenosis in patients with appropriate indications, leading to a DES usage rate of 30% in public hospitals.2 The MIG registry may provide an appropriate framework for a national PCI data registry. It satisfies most of Scott’s criteria, and many colleagues in other states have expressed interest in collecting similar data or collaborating in a joint registry. The limiting factor, as always, is funding. We join Scott in supporting the call for appropriate funding to be provided by government and professional societies to allow a national PCI registry to be established.

Christopher M Reid · Andrew E Ajani · David Eccleston

To the Editor: We read with great interest the case report by Barthwal and Herman,1 and agree with many of the points they raise. In-stent thrombosis after cessation of clopidogrel therapy in patients with drug-eluting stents (DES) is a significant problem in Australian medical practice, particularly in the perioperative period,2-4 as the case report by Barthwal and Herman confirms.1 It is often decided to cease clopidogrel therapy during the perioperative period to reduce the risk of bleeding. While clopidogrel given before cardiac surgery has been documented to increase transfusion rates and returns to the operating theatre,5 bleeding risk associated with clopidogrel and non-cardiac surgery remains poorly defined. Greater understanding of the risk of in-stent thrombosis after clopidogrel therapy withdrawal, and the risk of excessive bleeding if it is continued, in individual patients will provide rational perioperative planning and, hopefully, improved outcomes for our patients. Currently, the Cardiac Society of Australia and New Zealand has formed a multidisciplinary committee to create guidelines for the perioperative management of patients with coronary stents. In some instances, clopidogrel therapy may need to be replaced with alternative antithrombotic strategies to prevent in-stent thrombosis. We have proposed such a strategy, with excellent results so far.3,4 The complication of in-stent thrombosis was originally associated with a 50% mortality rate in the first series of cases reported.2 However, we have since reported three patients from Australia with in-stent thrombosis during the perioperative period, all of whom survived.4 We have set up a website (http://www. DESReporting.com) to enable clinicians worldwide to report perioperative management strategies and outcomes for patients with DES in their coronary arteries, and who undergo surgery.3,4 In view of the developing importance of perioperative late stent thrombosis, we strongly encourage reporting through this website. This will enable rapid accumulation of outcomes and associated antithrombotic strategies, with a view to dissemination and publication of the analysed data.

Myles M Conroy · Stephen N C Bolsin

To the Editor: The recent article by Barthwal and Herman highlights the problem of late stent thrombosis in a patient with a drug-eluting stent (DES) undergoing non-cardiac surgery (NCS).1 While the authors stated that clopidogrel therapy was ceased preoperatively and not restarted postoperatively, they did not say whether or not aspirin therapy was continued. In addition, emphasis was not placed on the role the surgical procedure played in this adverse cardiac outcome. Perioperative stent thrombosis as a result of discontinuation of dual antiplatelet therapy has been well described, to such an extent that the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association issued a joint advisory regarding the risk of premature cessation of dual antiplatelet therapy perioperatively.2 A prothrombotic state is well described in the perioperative period, as is a rebound hypercoagulable period following cessation of therapy with antiplatelet agents.3 Preoperative cessation of antiplatelet therapy by interventional teams is common in both routine and emergency procedures; this is sometimes unnecessary and not based on any evidence. Practitioners involved in ceasing antiplatelet therapy for procedures should be aware of the increased risk of major adverse cardiac events in patients with cardiac stents whose antiplatelet therapy is ceased prematurely.2 Duration of antiplatelet therapy following DES implantation is still a contentious issue, but the prothrombotic effect of NCS in addition to the baseline risk of late stent thrombosis in these patients is becoming less easy to ignore.4 Evidence-based guidelines for the perioperative management of patients with cardiac stents undergoing NCS are still to be established. Careful consideration should be given before perioperative cessation of therapy with antiplatelet agents in patients with coronary stents. Undertaking non-emergency surgery within 12 months of DES implantation should be avoided if possible.4,5

Simon J Pattullo · Rohan Jayasinghe

Objective: To determine the prevalence of elevated troponin levels after a marathon, and test for an association with reduced renal clearance.Design, setting and participants: Prospective observational study of entrants running the full (42 km) 2007 Perth Marathon, Western Australia.Main outcome measures: Elevated troponin levels (≥ 0.1 μg/L) after the race; pre- and post-race survey data, and biochemical parameters.Results: 27% of runners (92/346) enrolled in the study, of whom 88 (96%) completed it. Most were men (71%; 65/92); mean age was 43.1 years (SD, 9.8 years; range, 25–64 years) and mean body mass index (BMI) was 24.1 kg/m2. Raised troponin levels were seen in 32% of participants (28/88), the highest being 1.4 μg/L. The strongest predictor for developing elevated troponin levels was a decrease in weight (odds ratio [OR], 2.15; 95% CI, 1.27–3.65). Creatinine increase was also associated with elevated troponin levels (OR, 1.03; 95% CI, 1.01–1.06), but pre-race estimated glomerular filtration rate, age, sex, BMI, training factors, marathon experience and race time were not. Most runners (99%; 87/88) had elevated levels of ischaemia-modified albumin after the race.Conclusions: Troponin level increases were common among marathon finishers. The strongest predictors were weight loss and an increase in creatinine levels, suggesting that reduced renal clearance is an associated factor. Further study is needed to determine the clinical significance of these findings, and to understand the mechanism.

Kelley M Hubble MB BS · Daniel M Fatovich MB BS, FACEM · Jonathon M Grasko MB BCh · Samuel D Vasikaran MD, FRCPA

To the Editor: A 77-year-old woman with a history of idiopathic long-QT syndrome (presumed genetic) presented to hospital with a storm of defibrillator shocks from her implantable cardioverter defibrillator (ICD). She had a single-chamber Guidant Ventak Prizm VR, model 1850, and a Guidant ventricular lead, model 0148 (Guidant Corporation, Indianapolis, Ind, USA) implanted 12 months earlier after an episode of syncope. The lead had been implanted by left subclavian venous access. The patient’s postoperative course and responses to routine questioning indicated that the device was functioning normally. After presenting with device discharges, a 12-lead electrocardiogram showed oversensing suggestive of lead dysfunction. Stored electrograms from the defibrillator showed artifactual signals that were typical of lead disruption. These signals had triggered inappropriate detection of ventricular arrhythmia and subsequent device shocks (Box 1). The pacing threshold and lead impedance were normal. On close examination of the patient’s chest x-ray, a line of radiolucency was detected within the lead between the first rib and clavicle. At reoperation, the lead was extracted with minimum difficulty and the site of the insulation break was detected (Box 2). A new lead was implanted and the patient was discharged home well. Subsequent follow-up was uneventful. Lead failure can occur any time after implantation of an ICD, and should be suspected when patients present with inappropriate ICD discharges.1 This case illustrates oversensing as a result of the lead’s insulation being disrupted by crush compression between the first rib and clavicle. Alternative implantation techniques, such as cephalic vein cut-down or extrathoracic axillary vein puncture, have been suggested for venous access to avoid this complication.2 1 Stored electrograms from the patient’s implantable cardioverter defibrillator showed artifactual signals had triggered inappropriate detection of ventricular arrhythmia and subsequent device shocks (arrow) 2 Implantable cardioverter defibrillator lead after extraction showing the break in the insulation (arrow)

Chin V Hiew · James W Leitch

An otherwise healthy 28-year-old man had a cardiac arrest after a day of motocross racing. He had consumed excessive amounts of a caffeinated “energy drink” throughout the day. We postulate that a combination of excessive ingestion of caffeine- and taurine-containing energy drinks and strenuous physical activity can produce myocardial ischaemia by inducing coronary vasospasm. Clinical recordA 28-year-old male amateur motocross rider was admitted to Port Macquarie Base Hospital in August 2007 after having an out-of-hospital cardiac arrest. He had collapsed shortly after participating in a motocross race. An off-duty paramedic and nurse had been on hand, and effective cardiopulmonary resuscitation was commenced promptly. Paramedics arrived after about 20 minutes of resuscitation. The patient’s initial cardiac rhythm was recorded as ventricular fibrillation (Box 1). He was restored to sinus rhythm after receiving two 150 J biphasic direct-current shocks. Adrenaline 1 mg and atropine 1 mg were both given as adjuvants. He was intubated by paramedics and transported to hospital. Later, the patient recalled feeling well earlier in the day, until after his second race, when he developed dull constant retrosternal chest pain. He described this as being mild in intensity, with no radiation or associated symptoms. It settled within 30 minutes of sitting down to rest. He went on to participate in (and win) one more race that afternoon. He collapsed at about 3 pm, approximately 20 minutes after the last race. There had been no symptoms immediately preceding the collapse that he could recall. The patient had been well in the week preceding these events. He denied having any previous episodes of chest pain or syncope. He had a large breakfast on the morning of the motocross race and had remained adequately hydrated throughout the day. Further, he had consumed 7–8 cans of a caffeinated “energy drink” between 8 am and his collapse 7 hours later. He was otherwise fit and well and taking no regular medication. There was no family history of premature coronary disease, sudden cardiac death or unexplained syncope. He was a smoker with a six pack-year history of smoking. He denied alcohol misuse or illicit drug use. On arrival at hospital, the patient was intubated and sedated. He was haemodynamically stable, and physical examination was unremarkable. An initial electrocardiograph (ECG) showed sinus rhythm and elevated anteroseptal ST segments with reciprocal inferior ST depression. Chest x-ray showed a normal cardiac silhouette and no signs of pulmonary venous congestion. Computed tomography scans of the chest and brain were unremarkable, specifically excluding aortic dissection. Abnormal findings from laboratory tests included an elevated level of troponin I (0.24 mmol/L; reference range [RR], < 0.05 mmol/L) and a lowered potassium level (3.0 mmol/L; RR, 3.6–5.4 mmol/L). Results of a urinary screen for drugs of misuse, including amphetamines and cocaine, were negative. Screening for anabolic steroids was not performed. The provisional diagnosis was of anteroseptal ST elevation myocardial infarction. The patient was given thrombolysis with 50 mg of tenecteplase and commenced on an infusion of intravenous heparin. He was given loading doses of 300 mg of both aspirin and clopidogrel, and 25 mg of metoprolol, all by nasogastric tube. Hypokalaemia was corrected via intravenous infusion. The patient was transferred to a tertiary referral centre for cardiac catheterisation. On arrival there, an ECG showed evolving ischaemic changes across the anterolateral leads (Box 2). A troponin I peak level of 12.2 mmol/L was measured; his potassium level had normalised at 4.0 mmol/L. Echocardiography showed mild left ventricular enlargement and low-normal systolic function with a hypokinetic anteroseptal segment. Coronary angiography, performed on the same day, gave normal results. No attempts were made during angiography to induce vasospasm. The patient was cooled for 24 hours and extubated without difficulty. He was discharged after 6 days. At discharge, he was taking atenolol 50 mg, aspirin 100 mg, spironolactone 25 mg and perindopril 2.5 mg. On follow-up 2 months later, the patient reported that he had remained well and symptom-free. Echocardiography showed preserved global left ventricular function with a limited residual area of akinesis of the anteroseptal wall. He continued taking aspirin, perindopril and atenolol (reduced to 25 mg). He was advised not to compete in motocross races for 6 months, after which a stress echocardiogram was performed; this was negative for exercise-induced ischaemia. DiscussionWe postulate a possible role of excessive consumption of caffeinated energy drinks in triggering the life-threatening cardiac events described in this case. Although sudden cardiac death is an uncommon occurrence in people under the age of 40 years, when it does happen it is most often associated with the presence of structural heart disease, most frequently premature coronary atherosclerosis. Other common associations are hypertrophic obstructive cardiomyopathy and myocarditis.1,2 However, autopsy review studies have found that some 10%–12% of subjects in this age group have no obvious cardiac abnormalities on postmortem examination.1,2 Of identified causes in this group, many are familial sudden cardiac deaths or disorders of conduction, such as Wolff–Parkinson–White syndrome.3 Our patient had electrocardiographic and echocardiographic features indicative of transmural ischaemia localised to the anterior territory. This is suggestive of a regional rather than a global process, and suggests an ischaemic event rather than a primary arrhythmia. However, the angiogram did not show any significant coronary lesions. Although non-stenotic atherosclerotic plaques may rupture or denude and cause infarction through the formation of superimposed thrombi, which may have then been dissolved by the administration of thrombolytics, we believe that — considering this man’s relative youth — there is a distinct possibility that the underlying abnormality was coronary vasospasm. An arrhythmia, possibly triggered by the ingestion of stimulants in the presence of hypokalaemia and physical exertion, was a differential diagnosis. However, this would not account for the regional abnormality seen. The cause of this patient’s hypokalaemia is unclear, but may have been related to electrolyte losses from excessive sweating during exertion. This effect may have been exacerbated by the diuretic effect of caffeine. The role of illicit stimulants, especially cocaine, in causing coronary vasospasm in young people is well established.4 However, this patient denied cocaine use and returned a negative result on his drug test, making this an unlikely cause. The energy drink consumed by our patient contains 80 mg of caffeine (equivalent to one cup of espresso) per can. He drank seven or eight cans within 7 hours — up to 640 mg of caffeine in total. The drink also contains high doses of taurine (an amino acid) and glucuronolactone (a glucose metabolite), neither of which are considered to have significant toxicity, although there is a paucity of data.5,6 Caffeine is a naturally occurring xanthine derivative related to theophylline; it has a number of potential pharmacological actions on the cardiovascular system. Its primary mechanism of action is thought to be through competitive inhibition of adenosine receptors.7 It also induces catecholamine release, and causes a rise in intracellular calcium in myocytes through release of calcium from the sarcoplasmic reticulum, leading variably to smooth muscle contraction and relaxation.8-10 The role of caffeine in triggering arrhythmia is well established.8 There have been a number of case reports on hospitalisations or deaths due to caffeine toxicity, although the mechanism usually seems to be tachyarrhythmia and involves far higher doses than in this case.11,12 The median lethal dose in rats is 200–400 mg/kg.13 A 1997 case report described a young woman who suffered a myocardial infarction due to caffeine toxicity; however, this involved an oral dose of 20 g.14 In-vitro studies have shown that taurine has an inotropic effect on cardiac muscle similar to that of caffeine, and potentiates caffeine-induced muscle contracture. Few taurine toxicity studies have been performed, and there are insufficient data to suggest what an unsafe level of taurine consumption might be, if any.9,14 Both taurine and caffeine have been shown in vitro to have physiological effects on intracellular calcium concentration within vascular smooth muscle, and they could conceivably induce coronary vasospasm. In-vivo studies have demonstrated a capacity for caffeine to decrease myocardial blood flow during exercise.15 We postulate that, in physiologically predisposed individuals, a combination of excessive ingestion of caffeine- and taurine-containing energy drinks and strenuous physical activity can induce myocardial ischaemia by coronary vasospasm, with potentially fatal results. Caffeine has been removed from the list of prohibited substances in sport but remains on a monitoring program run by the World Anti-Doping Agency.16 Anecdotal reports suggest that the many caffeinated energy drinks now on the market are widely used by amateur and professional athletes to enhance their performance. We are concerned that a combination of exercise and the caffeine contained in these drinks may have the potential to trigger serious cardiovascular events. We accept that this is a single case, which does not and cannot establish causality. However, in the context of concerns reported in the media in recent years relating to similar events overseas, and in the presence of a plausible pharmacological mechanism, we believe that the potential dangers of these caffeinated energy drinks should be highlighted, and monitoring for future adverse events should be conducted. 1 Patient’s initial cardiac rhythm, showing ventricular fibrillation 2 Patient’s electrocardiograph on arrival at tertiary referral centre, showing evolving ischaemic changes across the anterolateral leads

Adam J Berger MB BS, BSc(Med) · Kevin Alford MB BS, FRACP, DDU

Best-practice guidelines mandate a full postmortem examination in these deaths to identify genetic causes and allow potentially life-saving interventions in the victim’s relatives The sudden and unexpected death of an apparently fit, healthy young person has a devastating effect on the family and community. If there is no adequate explanation for the death, the desperate sadness is usually compounded by frustration and fear that another family member may be struck. Yet, there is no uniform process in place in Australia and New Zealand to obtain a proper medical history of the victim, or to examine and investigate the victim’s family. Such a process could provide clues to the diagnosis and also identify previously undiagnosed genetic diseases. The lack of a consistent definition for sudden unexpected death in young people means there are few prevalence data. The best studies of incidence and causes of sudden natural death in 1–40-year-olds have been conducted by two forensic pathology centres in New South Wales.1,2 These suggest an annual incidence of around 20 per million — about 400 deaths per year in Australia. A striking feature was that the postmortem examination identified no specific cause of death in a third. This suggests an arrhythmic death caused by an underlying cardiac channelopathy, such as long-QT syndrome, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia.3 Clinical and genetic studies have confirmed the presence of these conditions in the Australian and New Zealand populations.4 They are the consequence of inherited dysfunction of cardiac cell channels (for potassium, sodium and calcium), which are involved in generating the cardiac action potential. The mode of death is ventricular tachycardia or fibrillation. The results of the two NSW pathology studies1,2 were surprising, as previous studies on sudden death in young athletes found that the most prominent causes were the structural heart diseases, hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Cardiac channelopathies, HCM and ARVC are all familial, with over 90% of cases inherited in an autosomal dominant fashion, meaning that 50% of first-degree relatives are potentially at risk. There is now good evidence that people with these conditions can benefit from interventions such as β-blockade and cardioverter defibrillators,5 so that identification of affected family members is potentially life-saving. Cardiological and genetic investigation of the relatives of young victims of sudden death can reveal an inherited heart disease in 40% of cases.6,7 To achieve this outcome, there is a need for a coordinated multidisciplinary team approach to the postmortem investigation of sudden deaths, including expert pathology, cardiology, clinical and molecular genetic assessment.8 The TRAGADY (Trans-Tasman Response Against Sudden Death in the Young) initiative was established in 2005, and comprises a group of over 50 highly motivated Australian and New Zealand health professionals, scientists and patient advocates who share the aim of reducing sudden death in the young caused by inherited heart diseases. The group has formulated a mission statement9 and, recognising the inconsistencies in postmortem practice across Australia and New Zealand, its first aim was to create a best-practice guideline for the postmortem investigation of sudden unexpected death in the young. This guideline has now been completed and formally approved by the Royal College of Pathologists of Australasia, and is available on the College website.10 A key message for the general practitioner is that a skilled postmortem examination is imperative after such deaths. There may be pressure from the family to avoid an autopsy, but ascribing such deaths to “heart attack”, for example, when there was some previous chest pain, misses the opportunity to make a proper diagnosis and potentially save the lives of other family members. Similarly, arrhythmic syndromes such as long-QT syndrome have been falsely diagnosed as epilepsy, and the death of any young person with epilepsy should be investigated in detail. Many families have suffered several sudden deaths because of a failure to investigate completely, as described on support group websites, such as that of the Australian Sudden Arrhythmia Death Syndromes Foundation (http://www.sads.org.au). Key points of the TRAGADY best-practice guidelines are summarised in the Box. Key points of best-practice guidelines on postmortem investigation of sudden death of a young person* A full postmortem examination should be completed in all cases of sudden unexpected death in young people (0–40 years). The investigation, ideally led by a pathologist, involves a team approach, including as a minimum: A person designated to liaise with the family; Specialist cardiology involvement with the family when non-cardiac causes are excluded; and Laboratories with molecular genetics, toxicology and metabolic expertise. A detailed antecedent clinical history must be obtained. A detailed and relevant family history must be obtained. Liaison with the family should be established early and be ongoing until a cause of death is ascertained. Skilled macroscopic and microscopic examination of the organs is required, particularly of the heart (especially right ventricular muscle), and the brain. This may require some specimens to be examined by other specialists. Adequate histological material must be obtained for review or, if necessary, referral. Tissue or blood suitable for DNA extraction must be obtained (paraffin-embedded tissue blocks are not suitable). * Devised by TRAGADY (Trans-Tasman Response Against Sudden Death in the Young) and endorsed by the Royal College of Pathologists of Australasia.

Jon R Skinner MD · Johan A Duflou MMed, FRCPA · Christopher Semsarian PhD, FRACP, FCSANZ

Combined with appropriate lifestyle modification and statin therapy, raising HDL levels may be an important strategy to reduce cardiovascular risk In the past two decades, we have made significant advances in the management of cardiovascular disease (CVD), with a dramatic reduction in cardiovascular events occurring in parallel with the widespread use of statins to lower low-density lipoprotein (LDL) cholesterol levels. Nevertheless, despite intensive use of statin therapy, a significant patient cohort remains at high risk of cardiovascular events, paving the way for new strategies to reduce their residual cardiovascular risk. One attractive target for such strategies is high-density lipoprotein (HDL) cholesterol. There is strong epidemiological evidence demonstrating the inverse relationship between the incidence of cardiovascular events in normal populations and serum HDL levels. Based on data from the Framingham Heart Study, the risk of myocardial infarction increases about 25% per 0.13 mmol/L decrement in serum HDL below median values.1 HDL levels are also predictive of coronary events in patients with known CVD across a range of LDL levels, as demonstrated in the Treating to New Targets trial, in which nearly 10 000 patients with established CVD were treated with statins.2 HDL levels were inversely predictive of time to first major cardiovascular event across the spectrum of LDL levels, including patients with treated LDL levels below 1.8 mmol/L, highlighting the predictive value of HDL levels independent of LDL levels. The atheroprotective effects of HDL have been attributed to its ability to mediate “reverse cholesterol transport”, where cholesterol in peripheral tissues is transferred via plasma to the liver for either recycling or excretion. More recently, the antioxidant and anti-inflammatory properties of HDL have been explored. In particular, intravenous preparations of HDL have been shown to dramatically reduce acute vascular inflammation in animal models, improve endothelial function (an important surrogate of cardiovascular risk), and promote atheroma regression and stabilisation in human studies.3 Moreover, because of the heterogeneity of human HDL, an appreciation of function as well as absolute concentration is becoming increasingly important. For example, HDL from subjects with diabetes has been shown to be less effective in its cholesterol-effluxing and anti-inflammatory capacity.4 Lifestyle modifications in the form of regular exercise, smoking cessation, weight loss and moderate alcohol consumption have each been shown to individually raise HDL levels by 5%–10%.5 Although statins are currently the cornerstone of lipid-modifying therapy, they raise HDL levels by only 5%–10%.6 On the other hand, fibrates have been shown to raise HDL levels by 10%–15%.7 Fibrates regulate HDL metabolism as ligands and activators of the nuclear transcription factor peroxisome proliferator-activated receptor-α.8 The benefits of using fibrates to raise HDL levels have been suggested by a number of randomised trials. For example, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) included 2531 patients with CVD, with an LDL level ≤ 3.6 mmol/L, HDL level ≤ 1.0 mmol/L, and triglycerides ≤ 3.4 mmol/L; patients were randomly assigned to receive treatment with gemfibrozil or placebo. At 5 years, the combined primary endpoint of cardiac death and non-fatal myocardial infarction occurred less often in the gemfibrozil-treated group, and the reduction in this endpoint correlated strongly with both serum HDL levels and degree of weight loss, but was independent of changes in LDL cholesterol or triglycerides concentration.7,9 Nicotinic acid is another effective HDL-raising drug, with an ability to raise levels by up to 30%. The HDL-Atherosclerosis Treatment Study (HATS) reported the effects of combined therapy with a statin and niacin on 160 patients with CVD, with an HDL level < 0.9 mmol/L and LDL level < 3.75 mmol/L.10 Compared with placebo, patients receiving simvastatin plus niacin were significantly less likely to experience a cardiovascular event. Furthermore, the magnitude of the reduction of clinical events with drug therapy was greater than that observed in studies of statins alone, suggesting that raising HDL levels provides additional protection beyond that attributable to simply lowering LDL levels.10 The side-effect profile remains problematic with this drug class, though development of extended-release preparations may overcome these issues. Most recently, a novel class of HDL-raising medications, the cholesteryl ester transfer protein (CETP) inhibitors, which prevent the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride, have been tested in large clinical trials. In particular, the CETP inhibitor torcetrapib was evaluated in the multicentre randomised Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which compared torcetrapib with placebo in more than 15 000 patients receiving atorvastatin.11 A significant increase in HDL levels (72%) and an additional decline in LDL levels (25%) below baseline after 12 months of torcetrapib therapy were seen. However, the trial was prematurely terminated due to a significant increase in cardiovascular events in the treatment arm; an “off target” effect on the aldosterone receptor leading to blood pressure elevations was postulated as a potential mechanism for this.11 Despite the setback experienced with torcetrapib, further studies are underway to develop more target-specific CETP inhibitors. Intravenous reconstituted HDL preparations and apolipoprotein A-I mimetic compounds are also in development. In the future, these compounds may be used to regress atheroma or suppress the arterial inflammation that is the hallmark of the acute coronary syndromes. Thus, raising HDL levels, in combination with optimising LDL cholesterol levels, blood pressure and glycaemic control, as well as appropriate lifestyle modification, represent important strategies for reducing residual cardiovascular risk. Such measures should see further improvements in clinical outcomes for patients with CVD.

Sanjay Patel MB BS, FRACP

Objective: To examine short- and medium-term outcomes of percutaneous coronary interventions (PCIs), with a focus on comparing drug-eluting stents (DESs) with bare-metal stents (BMSs).Design, setting and participants: Retrospective analysis of data from the Melbourne Interventional Group (MIG) registry, a large multicentre Australian registry. The study cohort consisted of 6364 consecutive patients undergoing 7167 PCIs between April 2004 and August 2007.Main outcome measures: Clinical events including death, myocardial infarction (MI), target lesion revascularisation (TLR), target vessel revascularisation (TVR) and major adverse cardiac events (MACE) (a composite of death, MI and TVR), at 30 days and at 12 months.Results: The cohort was predominantly male (74%), with a mean age of 64.7 years (SD, 12.0 years). DESs were used in 3482 (51.4%) of PCIs. In the overall cohort, rates of clinical events were low at 30 days: mortality (1.9%), MI (2.4%), TLR (2.0%), TVR (2.4%) and MACE (5.7%). At 12 months, event rates were: mortality (5.2%), MI (6.0%), TLR (5.8%), TVR (8.2%) and MACE (16.2%). Patients receiving DESs had similar mortality rates to those receiving BMSs (4.0% v 6.0%; P = 0.62 [propensity score-adjusted]); late thrombosis rates were also similar in the two groups (0.8% v 1.1%; P = 0.38). The proportion of patients receiving DESs fell significantly over time, from 54.9% in the first 24 months to 44.7% in the last 15 months of the study period (P < 0.01). Independent predictors of 12-month mortality included diabetes, renal failure, ST-segment-elevation MI and cardiogenic shock.Conclusion: Our clinical event rates were comparable with international registry outcomes. Rates of mortality and stent thrombosis were no higher in patients with DESs than those with BMSs. Although DESs were used in about half the procedures (preferentially for higher-risk lesions), recent trends suggest their use is in decline.

Andrew E Ajani MD, FRACP, FJFICM · Christopher M Reid BA, MSc, PhD · Stephen J Duffy FRACP, MRCP, PhD · Nick Andrianopoulos MB BS, MBiostat · Jeffrey Lefkovits MB BS, FRACP · Alexander Black MB BS, FRACP · Gishel New FRACP, FACC, PhD · Robert Lew MB BS, FRACP, PhD · James A Shaw MB BS, FRACP, PhD · Bryan P Yan MB BS, FRACP · Ronen Gurvitch MB BS · Ali Al-Fiadh MB BS · Angela L Brennan RN, CCRN · David J Clark MB BS, FRACP

To the Editor: The oculocardiac reflex is a potentially life-threatening phenomenon requiring prompt recognition and management. It is defined as a 20% or greater reduction in heart rate and/or the presence of arrhythmias during stimulation of the orbital contents.1 It is most commonly encountered in the context of paediatric squint surgery. We report its occurrence in a young healthy adult man after a traumatic facial injury. While being transported to hospital by ambulance, he had intermittent bradycardia, with a heart rate as low as 38 beats/min, and was administered a 1 g dose of intravenous atropine. His medical and ocular histories were unremarkable, and he had no history of unexplained syncope. In the emergency department, his heart rate remained low (40 beats/min) and his blood pressure was 122/52 mmHg. There was diffuse periorbital lid swelling and bony tenderness along the inferolateral orbital margin. He had restricted upgaze of his left eye; during this manoeuvre, his heart rate dropped to 20 beats/min and he developed hypotension, with a blood pressure of 92/48 mmHg. He was given three intravenous 500 μg boluses of atropine to improve his haemodynamic condition. An electrocardiogram showed sinus bradycardia, and subsequent recordings showed intermittent Mobitz II second-degree atrioventricular block. A computed tomography scan of the left orbit showed a moderately displaced fracture of the orbital floor involving the maxillary bone, with entrapment of orbital fat and the inferior rectus muscle (Box). Given the presence of the oculocardiac reflex with haemodynamic compromise, the fracture was immediately repaired surgically. Postoperatively, the patient’s blood pressure was 134/90 mmHg and his heart rate was 86 beats/min, with normal sinus rhythm. He recovered full eye movement, and no further oculocardiac reflex was recorded. He remained well 1 year after discharge. The oculocardiac reflex was first described by Aschner as a slowing of the radial pulse when pressure was applied to the eye.2 It is a rare but recognised occurrence among young healthy adults with orbital fractures. Clinical manifestations of the reflex may include bradycardia, hypotension, nausea, vomiting and syncope.3 The reflex is acknowledged as an important indication for immediate surgical repair of the orbit.4 In addition to reducing morbidity from the reflex, urgent repair is beneficial as it releases incarcerated soft tissue, leading to a more favourable outcome with less likelihood of squint.5 Cardiac decompensation due to traumatic facial injuries should alert clinicians to the possibility of the oculocardiac reflex and the need for urgent surgical intervention. Computed tomography scans of the patient’s left orbit Sagittal (A) and coronal (B) computed tomography scans showing left orbital floor fracture with entrapment of the inferior rectus muscle (arrows).

Vivek B Pandya · R Max Conway · Richard Conway

To the Editor: Streptococcus suis is an emerging zoonosis in humans and a common pathogen in Australian pigs.1 However, only two cases of human infection have previously been reported in Australia.2,3 We recently treated two Australian piggery workers, from the same town in New South Wales, for S. suis endocarditis. The first patient, a previously healthy 46-year-old woman, presented in October 2006 with a 3-month history of fatigue, anorexia, night sweats and weight loss of 20 kg. Her job involved hands-on work at a piggery. She was afebrile, with blood pressure of 145/50 mmHg, bilateral clubbing, splenomegaly, and a long diastolic murmur without evidence of heart failure. Transthoracic echocardiography confirmed severe aortic regurgitation associated with a vegetation. Blood cultures grew S. suis. The patient was treated with benzylpenicillin (1.8 g, 4-hourly for 6 weeks) and gentamicin (60 mg, 8-hourly for 2 weeks). Severity of aortic regurgitation necessitated aortic valve replacement. The second patient, a 58-year-old man, presented in January 2008 with headache, fever (38.7°C), neck stiffness and confusion. He had been unwell for 1 month with fevers, sweating, fatigue and weight loss of 6 kg. His job involved transporting pigs from local piggeries, including the one at which the first patient worked, to an abattoir, and involved direct contact with pigs. On admission, he was treated with ceftriaxone (2 g) and benzylpenicillin (2.4 g). Cerebrospinal fluid (CSF) examination showed leukocytosis (10 300 × 106/L; reference range, < 5 × 106/L) with 95% polymorphs. Scanty gram-positive cocci were visible, but there was no growth on culture of the CSF. Blood cultures grew S. suis. Transthoracic echocardiography revealed an aortic valve vegetation with trivial regurgitation. The patient was then treated with benzylpenicillin (1.8 g, 4-hourly for 4 weeks) and gentamicin (80 mg, 8-hourly for 2 weeks), and made a full recovery. Both cases were investigated by the NSW Department of Health, including assessment of workplace practices, staff education and rates of porcine infection at the piggeries and abattoir at which the patients had worked, but no significant factors for infection were identified. Since the first reported human infection with S. suis in Denmark in 1968,4 more than 400 cases have been reported, including an outbreak in China in 2005 that affected 215 people.5 The most common manifestations are meningitis (affecting 72.5% of patients) and bacteraemia (24.2%); endocarditis is relatively uncommon (1.1%).5 In a series of 16 cases of S. suis endocarditis, the mean period between onset of symptoms and diagnosis was 23 days, and seven patients required valve replacement.6 Similarly, our patients had subacute presentations: severe aortic regurgitation and secondary meningitis. In Australia, it is likely that there have been other S. suis infections in humans that have gone unrecognised because of mild presentations, difficulties with laboratory diagnosis, and empirical treatment of unrecognised infection. While it is unlikely that S. suis is a common zoonosis in Australia, these cases show that it is an occupational hazard in Australian piggeries, with potential public health, animal health and medicolegal implications.

Karina J Kennedy · Assad A Jadeer · Chong W Ong · Sanjaya N Senanayake · Peter J Collignon

A decade of research has led to more precise guidelines for a complex health problem It has long been considered that all patients with heart conditions that predispose to infective endocarditis should receive antibiotic prophylaxis when undergoing procedures that can lead to bacteraemia with organisms known to cause endocarditis. However, the evidence for such action is surprisingly poor.1 It is based on isolated case reports of endocarditis following dental or other procedures, and on theoretical considerations, rather than the results of randomised controlled trials. The American Heart Association (AHA) has published guidelines for endocarditis prophylaxis since 1955. In Australia, all editions of the Antibiotic guidelines (now Therapeutic guidelines: antibiotic, version 132) have also included recommendations for antibiotic prophylaxis against endocarditis. Of necessity, these guidelines have been complex, as three major variables were considered — the lifetime risk of endocarditis due to the underlying heart condition, the likelihood and nature of bacteraemia following the procedure, and the risk of adverse effects from antibiotic therapy.2 The lifetime risk associated with the cardiac condition was divided into three risk categories (high, medium and low), and the likelihood of bacteraemia from a procedure was similarly divided into risk categories. Thus, prophylaxis has been firmly recommended for patients with an underlying heart condition who are at high risk of endocarditis and are undergoing a procedure that has a high risk of leading to significant bacteraemia. Conversely, it has not been recommended for patients with conditions who are at low risk of endocarditis and are undergoing procedures with a low risk of leading to significant bacteraemia. Prophylaxis has been “possibly” and “probably” recommended for various intermediate-risk combinations. Over the past 10 years, thinking has changed for three main reasons. First, there is now strong evidence that bacteraemia with endocarditis-causing organisms frequently occurs following everyday activities, such as tooth brushing.3-6 Second, it has been recognised that very few cases of endocarditis can reasonably be attributed to a preceding procedure and are more likely to have resulted from everyday activities. Third, it has been realised that we should be more concerned about patients who are likely to have a poor outcome if they develop endocarditis than those who are at high risk of developing endocarditis at all.1 In the context of this change in thinking, organisations around the world (including the AHA) have published new guidelines for endocarditis prophylaxis that differ considerably from the previous versions.1,7,8 In Australasia, at the request of the Heart Foundation (formerly, the National Heart Foundation of Australia) and The Cardiac Society of Australia and New Zealand, Therapeutic Guidelines Limited convened an expert group to reconsider its guidelines. This expert group updated the Australian guidelines largely along the lines of the new AHA guidelines, continuing a trend to reduce the categories of patients for whom prophylaxis is recommended, while still specifying procedures for which it is required. In summary, the changes are: The list of heart conditions for which endocarditis prophylaxis is recommended is much shorter and is largely limited to conditions in which foreign material is implanted in the heart. In this setting, endocarditis is very difficult to eradicate, so an adverse outcome is more likely. Of note, the list does not include rheumatic valvular heart disease in non-Indigenous patients or mitral valve prolapse. The list of dental and respiratory procedures for which endocarditis prophylaxis should be given is more precise. For some dental procedures, the guidelines emphasise that the need for prophylaxis relates more to the circumstances of the procedure and the patient’s periodontal condition than to the procedure itself. The list of gastrointestinal and genitourinary procedures is similarly precise, and includes procedures that also have a requirement for surgical antibiotic prophylaxis, or which are being carried out in the presence of a related infection. The only significant difference between the new Australian guidelines and the AHA guidelines is that rheumatic valvular heart disease in Indigenous Australians has been retained in the list of cardiac conditions for which prophylaxis should be given. Experienced clinicians have the strong impression that the outcome of endocarditis in Indigenous Australians is poorer than in non-Indigenous Australians, possibly in part because of delays in diagnosis and therapy. Studies are currently being undertaken to determine whether this clinical impression is correct, but until the results are available, it was thought wise to retain this indication. These new guidelines might cause confusion at first, particularly when patients who previously received prophylaxis are advised that it is no longer necessary. To help ease this confusion, the new guidelines state that it is reasonable to give prophylaxis to patients who have previously received it and would prefer to be given it again. The new Australian guidelines are available free of charge on the Therapeutic Guidelines website (http://www.tg.com.au) and in its electronic publications (eTG complete and miniTG). The print versions of Therapeutic guidelines: antibiotic and Therapeutic guidelines: oral and dental will be updated as the new editions are published. We recommend these guidelines to Australian practitioners and trust they will find them useful and decide to follow them.

Robert F W Moulds BMedSc, PhD, FRACP · Melanie S Jeyasingham BPharm, MPS

Trials measuring major cardiovascular events as an endpoint are the best evidence to determine if an intervention such as ezetimibe conveys benefit At an American College of Cardiology meeting in Chicago earlier this year, the long-awaited results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial were finally presented, with simultaneous publication in the New England Journal of Medicine.1 ENHANCE was a double-blind, randomised controlled trial comparing 80 mg of simvastatin plus placebo daily with 80 mg of simvastatin plus 10 mg of ezetimibe daily in patients with familial hypercholesterolaemia. The primary trial endpoint was change in mean carotid and femoral intima-media thickness (IMT) over a 24-month period (Box). Although the trial finished in mid 2006, the results were not forthcoming from the United States sponsors (Merck and Schering-Plough) until a US Congressional Committee required the companies to reveal them, which they did in the form of a press release earlier this year.2,3 In the combined-therapy group, the benefit expected from a 17% lower level of low-density lipoprotein cholesterol (LDL-C) due to ezetimibe was not realised — mean IMT did not differ between the two groups. There was progression in mean carotid IMT (CIMT) in both groups (P = 0.02 for simvastatin-only group and P < 0.01 for combined-therapy group). Regression occurred in 44.4% of the simvastatin-only group and 45.3% of the combined-therapy group. New lesions (> 1.3 mm CIMT) occurred in 2.8% of the simvastatin-only group and 4.7% of the combined-therapy group (P = 0.20). Various possible explanations for these unexpected results were given by the study authors.1 The first was that ezetimibe is not protective for the vasculature, in spite of its significant lowering of LDL-C levels; the second was that the methodology used to measure IMT was insufficient to detect small changes in response to the therapy; and the third was that the population with familial hypercholesterolaemia had virtually normal baseline IMT due to their previous extensive treatment with statins, which may have rendered their arteries relatively unresponsive to further LDL-C reduction. The first explanation is unlikely because ezetimibe has shown no previous evidence of vascular toxicity, and a recent study in which statin–ezetimibe therapy was used as part of an aggressive management algorithm showed regression of CIMT (although this was not a randomised trial of ezetimibe use).4 The second explanation is also unlikely, although ENHANCE did not employ electrocardiogram gating of images to control for image variability during the cardiac cycle, and used single-frame technology rather than cine-loop technology to improve image quality.2 The third explanation seems the most likely, for several reasons. Previous studies of CIMT have shown either lack of progression (ie, stabilisation) or regression with lipid-modifying therapy, primarily related to changes in LDL-C levels.5 Unlike ENHANCE, these studies involved patients with increased baseline CIMT and had inclusion criteria for CIMT. Data also presented at the American College of Cardiology meeting, but yet to be published, showed that statin-naïve patients had no significant change in CIMT with either therapy.2 Baseline CIMT in this group was also near-normal — an unusual finding for true familial hypercholesterolaemia patients. However, no data were presented to confirm the presence of LDL receptor mutations. If this explanation is correct, perhaps ENHANCE could never have shown a positive result, because most patients had been treated with statins for decades before enrolment in the trial. Evidence for this theory comes from the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) extension study, in which patients in the earlier ASAP trial were continued on 80 mg of atorvastatin daily for a further 2 years.6 Patients in the original atorvastatin group (in whom there had been regression of 0.031 mm) showed no further change in CIMT, while those originally in the simvastatin 40 mg group (in whom there had been progression of 0.036 mm) showed significant regression.6 The results of the ENHANCE trial are important because ezetimibe accounts for a significant proportion of lipid-lowering medication prescriptions around the world (3% in Canada, similar to use in Australia; and 15% in the US).7 Ezetimibe was approved for marketing in the US about 5 years ago, based on its efficacy in lowering LDL-C levels rather than efficacy in reducing major adverse cardiovascular events or improving surrogate endpoints such as CIMT. This situation is the opposite for newer drugs such as torcetrapib, which, in spite of increasing high-density lipoprotein cholesterol levels by more than 50%, was withdrawn from the market because of negative results in trials investigating its effects on CIMT and major adverse cardiovascular events.8,9 So, where do we go from here? The first caveat is not to abandon the modern cholesterol hypothesis (“the lower the LDL-C, the better”) after one negative trial. Only trials measuring major adverse cardiovascular events as an endpoint can definitively answer the question of whether a given intervention conveys benefit, regardless of changes in surrogate markers like CIMT or plaque size. We must therefore await the results of a clinical endpoint trial with ezetimibe, which adds a further 15%–20% reduction in LDL-C levels to that achieved by statin therapy, and which should reduce major adverse cardiovascular events by a similar percentage. IMPROVE-IT is a trial comparing cardiovascular death, major coronary events and stroke in 18 000 patients with recent acute coronary syndromes treated with 40 mg of simvastatin either alone or in combination with 10 mg of ezetimibe.2 It is due to be reported in 2012. Until then, it seems prudent to continue clinical practice on the basis that the cholesterol hypothesis is alive and well, and to continue using ezetimibe in statin-intolerant patients and those taking maximum-tolerated doses of statins who have not yet achieved LDL-C target levels.10 Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study1 720 patients with familial hypercholesterolaemia Baseline: low-density lipoprotein (LDL) cholesterol, 8.2 mmol/L; high-density lipoprotein (HDL) cholesterol, 1.2 mmol/L Compared simvastatin 80 mg + placebo daily with simvastatin 80 mg + ezetimibe 10 mg daily Primary endpoint was mean intima-media thickness (IMT) of carotid and femoral arteries with B-mode ultrasonography End of study: mean LDL cholesterol 16.5% lower in ezetimibe group (P < 0.01); no difference in HDL cholesterol No difference between treatment groups in carotid IMT after 2 years (P = 0.29): + 0.0058 mm in simvastatin–placebo group + 0.011 mm in simvastatin–ezetimibe group Side-effect and safety profiles similar in both groups

Ian R Hamilton-Craig MB BS, PhD, FRACP

Objective: To determine how well the current Pharmaceutical Benefits Scheme (PBS) eligibility criteria for subsidy of lipid-lowering drugs compare with current national guidelines for determining the population at high risk of developing cardiovascular disease (CVD).Design and participants: Analyses of the population-based, cross-sectional Australian Diabetes, Obesity and Lifestyle (AusDiab) study, conducted in 1999–2000. The 1991 Framingham risk prediction equation was used to compute 5-year risk of developing first-time CVD in 8286 participants aged 30–74 years with neither CVD nor diabetes. Based on the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines, people with either 5-year CVD risk ≥ 15% or with 5-year CVD risk of 10%–< 15% and the metabolic syndrome were defined as having estimated high absolute CVD risk.Main outcome measures: 5-year CVD risk; estimated population with high CVD risk.Results: Among participants without prevalent CVD or diabetes, 7.9% of men and 1.5% of women had a 5-year CVD risk ≥ 15%. Of the estimated residential Australian population in 2000 aged 30–74 years without CVD or diabetes, 717 000 people were considered to be at high absolute CVD risk. Among the high-risk AusDiab participants without CVD or diabetes, only 16.9% of men and 15.4% of women were being treated with lipid-lowering drugs. Of the 9.6% of participants free of CVD and diabetes who were untreated but eligible for subsidy under PBS criteria, only 27.4% had an estimated high absolute CVD risk.Conclusion: Strategies for CVD prevention using lipid-lowering medications can be improved by adoption of the absolute-risk approach.

Lei Chen MD, MMed · Sophie L Rogers MEpi · Stephen Colagiuri MD, FRACP · Dominique A Cadilhac MPubHlth, PhD · Timothy H Mathew MB BS, FRACP · Andrew N Boyden BM BS(Hons), MPH, FRACGP · Anna Peeters BSc(Hons), PhD · Dianna J Magliano MPH, PhD · Jonathan E Shaw MD, MRCP, FRACP · Paul Z Zimmet MD, PhD, FRACP · Andrew M Tonkin MB BS, MD, FRACP

Earlier this year, two industry-sponsored advertising campaigns for cholesterol awareness that target the general public were launched in Australia. These campaigns aimed to alert the public to the risks associated with having high cholesterol and encouraged cholesterol testing for wider groups than those specified by the National Heart Foundation. General practitioners should be aware of the potential for the two campaigns to confuse the general public as to who should be tested, and where. The campaign sponsors (Unilever Australasia and Pfizer) each have the potential to benefit by increased market share for their products, and increased profits. These disease awareness campaigns are examples of what is increasingly being termed “condition branding” by pharmaceutical marketing experts.

Danika V Hall BA, MEd · Megan D Cobcroft · John W Ketelbey