Cardiovascular diseases

In reply: We agree that there are no guidelines defining torsade de pointes based on intracardiac electrograms, but there are several reasons why the likelihood of torsade de pointes (as opposed to any other arrhythmia) in our patient is high. The electrogram shows the arrhythmia just before delivery of direct current shock, this being about 30 minutes after the patient took her first ever dose of loratadine. There are marked variations in electrogram morphology, despite minimal variation in RR interval, in a short strip of recording in this patient with documented QT prolongation. Further, she had no history of monomorphic ventricular tachycardia, no inducible monomorphic ventricular tachycardia at electrophysiologic examination, and no evidence of structural heart disease. Neither was a mechanism for supraventricular arrhythmia identified. The absence of initiating beats showing pause-dependence is unfortunate, but this is not provided by the generation of device implanted in this patient. Hence, we believe the word "probable" is an apt description for the observation made.

Dennis L Kuchar · Bruce D Walker · Charles W Thorburn

Measurement of clinical performance. Practical approaches in acute myocardial infarction. Robert West, Robin Norris (editors). London: Royal College of Physicians, 2001 (viii + 128 pp). ISBN 1 86016 152 9. Evaluating the quality of clinical care is now the accepted, indeed mandatory, duty of all who practise medicine. Medical colleges have introduced programs for maintaining professional standards, and many of these feature clinical audit as a necessary activity. For the busy clinician, however, finding both the time and the means to perform accurate and consistent audits poses major challenges. This work, from the Royal College of Physicians (RCP), offers pragmatic strategies at both a national and a local level for conducting meaningful clinical audit. While focusing on the care of patients with myocardial infarction, the messages contained in this book can apply to any area of medicine. The first half deals with clinical governance (UK style): use of performance indicators and league tables; the choice between process or outcome measures; and an overview of national benchmarking projects in the UK dealing with coronary heart disease, asthma and stroke. The second half covers the practicalities of auditing the care of patients with myocardial infarction, as exemplified by the Myocardial Infarction National Audit Project. This ambitious project aims to recruit all hospitals in England and Wales, and uses a nationally funded, RCP-sponsored data collection, analysis and reporting system which is standardised, computer-based and centrally coordinated. Such a system relieves local clinicians of the need to develop their own audit system from the ground up. The authors of each chapter speak authoritatively from personal experience about the good and bad in conducting clinical audit, and offer advice on what to avoid. Finding a "how to" book in performance measurement that is short (128 pages), easy to read, inexpensive and rich in practical applications is a rare delight for this jaded healthcare researcher. My only regret — I would have liked a little more on how to use the results of audit to full effect in improving quality of care at the local level. Ian A ScottDirector of Internal Medicine Princess Alexandra Hospital, Brisbane, QLD

Ian A Scott

We need to derive absolute cardiovascular risk functions based on contemporary Australian data The accurate estimation of risk for future disease events is critical to the determination of the benefit–risk ratio and the most cost-effective use of preventive therapies (Box 1). This is particularly relevant for cardiovascular diseases (CVD), which are the leading cause of deaths in Australia (40% of total deaths), and in 1993–1994 accounted for the largest proportion (12%, or $3.9 billion) of total annual recurrent health expenditure.3 (This proportion is now almost certainly greater.) Expenditure on cardiovascular drugs under the Pharmaceutical Benefits Scheme totals $1.2 billion annually, $629 million of this on lipid-lowering drugs, especially statins.4 Accurate assessment of the likelihood of future events would optimise resource allocation by targeting patients at higher risk.5 In this context, the work of Simons et al, reported in this issue of the Journal (page 113),6 is very important. In their ongoing Dubbo Study (which commenced in 1988 and involved 2805 men and women aged 60 years and older when first assessed), the authors evaluated a risk function for coronary heart disease (CHD) prediction developed from a longitudinal cohort study in Framingham, Massachusetts — the Framingham Study. They also derived a risk function for future CVD events, including stroke as well as CHD, by modelling data from the Dubbo cohort. The Framingham risk functions7-9 are widely used and form the basis of a New Zealand cardiovascular risk calculator,10 itself proposed as the absolute risk measurement tool in the recent lipid guidelines of the National Heart Foundation/Cardiac Society of Australia and New Zealand.11 The Framingham cohort consists primarily of white, middle-class individuals. The equation was derived from calculations based on age, sex, cigarette smoking status, diabetes status, and blood pressure, cholesterol and HDL cholesterol levels only. The Framingham measurements were also made some time ago before the dramatic increase in the prevalence of diabetes,12 and indeed Framingham included low numbers of people with diabetes. In essence, the study by Simons et al determined the applicability of observations made in another time and another place to an Australian population. They showed that the Framingham equation accurately predicted overall 10-year incidence of "hard" CHD endpoints (myocardial infarction or coronary death). This supports previous validation work with the Framingham equation in the Busselton study.13 However, the Busselton study is now over 20 years old, while the Dubbo cohort included only older individuals. Therefore, while these validation studies are important, it would be more relevant to derive predictive equations from data obtained from a representative and contemporary Australian cohort. This would acknowledge the variety of ethnic groups in Australia and the current mix of known and unknown risk factors. As the Framingham equation correctly predicts risk in only about 80% of cases,14 there is considerable interest in "novel" risk factors (eg, high sensitivity C-reactive protein) and techniques for imaging the arterial wall. Future research must examine the degree to which these elements might improve the ability to correctly identify those at risk. With the shift of treatment guidelines from individual risk thresholds for treatment to decisions based on multivariable absolute risk, the logical extension of this is to estimate treatment efficacy or effectiveness in terms of absolute treatment benefit. For example, the benefits of cholesterol lowering in terms of improving average life expectancy have previously been estimated.15 This approach would provide more meaningful information to both patients and clinicians, as well as allowing the non-cardiovascular benefits of modifying risk factors such as tobacco smoking, physical inactivity, and unhealthy diet to be taken into account. Data such as those from the Dubbo study have important implications for current Australian guidelines and practice (Box 2). Treatment decisions based on individual risk-factor thresholds are inadequate. The Dubbo study assesses the validity of the Framingham risk prediction equations in the elderly and provides an Australian risk equation for the same age group. Further work should be done to validate these equations in a wider contemporary population and to determine the extent to which new risk factors may improve assessment of risk. This should not, however, preclude swift measures to implement the use of absolute risk, as well as consideration of absolute treatment benefit, as ways of guiding treatment decisions in clinical practice. 1: Why focus on absolute risk of cardiovascular disease? Individuals with levels which fall in the highest decile for systolic blood pressure, cholesterol and body mass index account for only 20%–30% of the total number of cases of stroke, ischaemic heart disease and diabetes.1 Interventions based on elevated levels of a single risk factor may allocate treatment to individuals with little chance of gain because of low absolute risk.2 Absolute risk is the likelihood of developing an event(s) over a particular time period. Absolute risk equations acknowledge the multifactorial causation of cardiovascular disease, the sex difference in risk and the steep increase in risk with ageing. Epidemiological studies have shown a continuum of risk for increasing levels of risk factors, such as blood pressure, total cholesterol and HDL cholesterol levels, which is acknowledged in absolute risk equations. 2: Recommendations for current guidelines, practice and research in cardiovascular disease Treatment guidelines should place greater emphasis on absolute risk estimation in those without manifest cardiovascular disease (CVD). Linking estimates of the likely absolute benefit of interventions with calculation of absolute risk should reinforce the rationale for lifestyle measure for all individuals and pharmacological treatment for those at higher risk. Prediction of overall CVD risk over 5 (or 10) years should be the endpoint, as opposed to risk of coronary heart disease alone. Components of a composite CVD endpoint should be re-examined and possibly restricted to "hard" outcomes such as CVD death, non-fatal myocardial infarction and non-fatal stroke. Agreement on and adoption of a standardised approach would facilitate implementing absolute risk prediction in Australia. Future studies should include variables that might further improve risk prediction (eg, waist circumference, microalbuminuria, high-sensitivity C-reactive protein). Absolute risk assessment is likely to be implemented most effectively using electronic tools which can link to other national initiatives. Absolute risk assessment will not only optimise health gains, but will result in more cost-effective treatment and prevention.

Andrew M Tonkin MB BS, MD, FRACP · Stephen S Lim BA, BSc · Henrik Schirmer MD, PhD

Objectives: To evaluate a Framingham risk function for coronary heart disease in an elderly Australian cohort and to derive a risk function for cardiovascular disease (CVD) in elderly Australians.Design and setting: Analysis of data from a prospective cohort study (the Dubbo Study) in a semi-urban town (population, 34 000).Participants: 2805 men and women 60 years and older living in the community, first assessed in 1988, and a subcohort of 2102 free of CVD at study entry.Main outcome measures: Incidence of CVD (myocardial infarction, coronary death or stroke) over 5 and 10 years.Results: A Framingham risk function assessing "hard" coronary heart disease (ie, myocardial infarction or coronary death) accurately predicted 10-year incidence in men and women aged 60–79 years who were free of prevalent CVD or diabetes at study entry. In a multiple logistic model, CVD incidence was significantly predicted by age, sex, taking antihypertensive medication, blood pressure, smoking, total cholesterol level and diabetes. For a given age and cholesterol level, CVD risk over 5 years was doubled in the presence of antihypertensive medication or diabetes, increased by 50% with cigarette smoking, and halved in women compared with men.Conclusions: We have derived a simple CVD risk function specifically for elderly Australians that employs risk factors readily accessible to all medical practitioners.

Leon A Simons MD, FRACP · Judith Simons MACS · Latha Palaniappan MD, FACP · Yechiel Friedlander PhD · John McCallum DPhil

To the Editor: Interpretation of the report describing the first death attributed to the Irukandji syndrome should be tempered by the fact that significant unstated assumptions have been made in attributing the cause of death to a jellyfish.1 While envenomation by a jellyfish remains the likely diagnostic possibility, no evidence is presented that unequivocally confirms a jellyfish as the lethal agent. Several methods could have been used to support or confirm the diagnosis of jellyfish envenomation, including sampling of nematocysts from the victim's skin (before or after death), jellyfish capture, or reports of other similar, but less severe, stings from the same beach around the time the victim was stung. In severe jellyfish envenomation, attempts are often made to harvest nematocysts from patients' skin, most commonly by skin scraping or by sticky tape sampling.2 Recovered nematocysts may help to identify the species, and confirm the diagnosis.3 Although successful nematocyst recovery is uncommon in Irukandji syndrome, it is disappointing that "no attempt was made to sample nematocysts"1 given the relative simplicity of the procedure and the importance of this case. The authors state that "no sting site was clearly delineated",1 but then go on to say that there were, in fact, areas of "skin flushing and intermittent diaphoresis"1 over a significant period of time. Sticky tape sampling of these areas may have yielded nematocysts, allowing positive species identification. Postmortem skin sections have also been employed in Chironex fleckeri fatalities, and have shown nematocyst barbs on the victim's skin.4 Postmortem examination may also have revealed other contributing factors. I am particularly interested in the assertion that almost every Irukandji syndrome patient in the Whitsundays develops a "rise in cardiac troponin levels".1 In fact, the cited article makes no mention of troponin, simply stating that CK-MB (creatine kinase isoenzyme) levels "can be abnormal",5 and that "some severe cases [of Irukandji syndrome] may have a CK-MB [level] well above the normal range".5 Many aspects of the diagnosis and treatment of jellyfish envenoming remain controversial. Accurate reporting of unusual cases is thus of the utmost importance.

Paul M Bailey

Chlamydia pneumoniae has been detected in atherosclerotic plaques, while seropositivity to this organism confers a slightly increased risk of coronary events. However, no aetiological link has been established; a major difficulty when investigating this link is the lack of a gold standard for diagnosing chronic vessel infection. The outcomes of case–control studies and prospective trials of macrolides in treatment and prevention of cardiovascular disease have been ambiguous but suggest a short-term preventive effect. Whether this is due to the antimicrobial or anti-inflammatory activity of the macrolides is unknown. Larger and longer prospective trials currently under way may provide better insight into the association of C. pneumoniae with cardiovascular disease. At present, there is no justification for treating cardiovascular disease with antibiotics.

Mikkel M Larsen BSc · Birgitte Moern MD, PhD · Paul L Andersen MD, DMSc · Lars J Ostergaard PhD, DMSc · Andrew Fuller FRACP

To the Editor: Advocating implementation of evidence-based clinical practice guidelines is one aspect of the current drive to provide quality healthcare across different centres. Quality theory demands that outcomes are continuously sought and that practices are modified accordingly — the "quality loop". Therefore, Scott and Harper are to be applauded for their pursuit of improved outcomes, not just improved processes, in studying guideline-discordant care in acute myocardial infarction.1 I believe that this type of study, which objectively demonstrates the role of practice guidelines in "real world" practice, is very important. However, as a geriatrician, my patient population is unlikely to intersect with populations enrolled in large cardiology trials (eg, those for thrombolysis in myocardial infarction).2,3 Comorbidities, such as renal impairment, cognitive impairment and poor functional status at baseline, were not explicit exclusion criteria, but, when present, would have reduced an individual's chance of being enrolled. These types of comorbidities are likely to be associated with a reluctance on the part of patients and physicians to pursue life-prolonging interventions. They are also likely to be associated with poorer outcomes, whatever the intervention. Therefore, I believe that these non-cardiac comorbidities are potential confounders for study designs, such as that of Scott and Harper.1 Older age per se has been well studied in the cardiology literature on management of myocardial infarction. However, in the literature on adherence to guidelines, few studies have attempted to fully identify the non-cardiac-related characteristics of those receiving guideline-discordant care. Krumholz et al reported that altered mental state is one factor, and that, of a large "real-world" cohort aged 65 or more, only 8% were considered ideal candidates for thrombolytic therapy.4 Quality healthcare involves multiple dimensions, including both personal and process factors. Practice guidelines are valuable tools to reduce practice variation, but we need to continue to evaluate whether they can be applied as broadly as may be advocated. Surely, evidence-based guidelines can only be confidently applied to situations for which an evidence base exists. It will be important to test the application of guidelines in many settings, with attention to potential confounders, and, in particular, to outcome measures.

Kristen J Pearson

In reply: We thank Pearson for her kind comments and agree the design of our study1 prevented identification of all patient factors that may, quite reasonably, impact on clinicians' decisions to administer specific treatments to older patients with acute myocardial infarction (AMI). These factors may also have precluded such patients from enrolment in clinical trials, the results of which underpin recommendations within clinical practice guidelines. On the other hand, we know advancing age is an independent predictor of increased mortality after AMI, with several possible causes: age-related reductions in protective mechanisms (such as myocardial preconditioning),2 presence of cardiac and non-cardiac comorbidities unaffected by treatments for AMI,3 and — the focus of our study — underuse of effective therapies in the absence of discernible contraindications.4,5 While cognitive impairment, renal dysfunction and poor functional status may dissuade patients and/or clinicians from pursuing "aggressive" management, we have no evidence that these factors, singly or in combination, necessarily attenuate the benefits of specific interventions for AMI in patients at high baseline risk of cardiac death.6 We also adjusted mortality comparisons between concordant- and discordant-care groups for multiple measures of illness severity at presentation which predict a poor prognosis. Nevertheless, we support calls for more randomised trials of treatments for AMI and other conditions in older patients with liberal, "real-world" inclusion criteria in determining absolute risks and benefits of intervention in the presence of multiple comorbidities and impaired function.

Ian A Scott · Catherine M Harper

The 14th World Congress of Cardiology, held in Sydney 5–9 May 2002 (the first time ever in the antipodes), was a joint meeting with the 50th anniversary meeting of the Cardiac Society of Australia and New Zealand (CSANZ). The Congress is the principal meeting of the World Heart Federation, a body comprising all of the world's cardiac societies and heart foundations. Delegates came from 115 countries, and there was a total registration of just over 9000. More than 3000 abstracts were received from investigators in 82 countries. In addition to focusing on developments at the cutting edge of cardiovascular disease, the Congress explored themes such as the world burden of cardiovascular disease and the likely rise of this burden in the 21st century, particularly in developing countries — a prospect of particular concern to the World Heart Federation. Worldwide issuesIschaemic heart disease is the leading cause of death in developed countries. While age-adjusted mortality from the disease is gradually falling in developed countries, including Australia, it is set to become an epidemic in developing countries, and over the next 20 years will probably become the most important global health problem. This was put into perspective by Salim Yusuf (Director of Cardiology, McMaster University, Hamilton, Canada). George Mensah (Head, Cardiovascular Division, Centers for Disease Control and Prevention, Atlanta, USA) highlighted the fact that the epidemic of ischaemic heart disease is driven by tobacco use, particularly in Asian and former Eastern European countries, while Stephen Colagiuri (Director of Endocrinology, Prince of Wales Hospital, Sydney) emphasised the rapid increase in diabetes that is occurring with population aging and increasing overweight and obesity. David Wood (Professor of Preventive Cardiology, National Heart and Lung Institute, London, UK) made the point that both prevention and treatment must translate into practice the large scientific and clinical evidence base of effective measures, but that we should also focus on developing tools to assess future absolute risk of cardiovascular disease rather than concentrating only on individual risk factors. These measures should support compliance with therapeutic regimens (Martha Hill, Dean of Nursing, Johns Hopkins University, Baltimore, USA) and, very importantly, consider the underlying psychosocial and socioeconomic determinants of disease (Michael Marmot, Professor of Epidemiology and Public Health, University College, London, UK), particularly in the vastly populated poor regions of Asia (Sania Nishtar, Director, Heartfile, Pakistan). AtherosclerosisInflammation is now regarded as a key process in the development of atherosclerosis and the destabilisation and rupture of plaques in acute coronary syndromes and cardiac death. The role of activated macrophages and T lymphocytes in secreting matrix metalloproteinases and tissue factor during plaque rupture was highlighted.1 This information has almost immediate practical application: diagnostic assays for inflammatory markers such as C-reactive protein are predictive of risk of myocardial infarction, stroke and death in population studies. Valentin Fuster (Director, Weiner Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA) also emphasised the need to find a systemic solution to atherosclerosis, possibly through novel approaches to reducing the effects of inflammation. In a plenary session on presymptomatic detection of atherosclerosis, the importance of defining high-risk populations was emphasised (Sidney Smith, Chief Scientific Officer, American Heart Association, Dallas, USA), as the first manifestation of vascular disease is often a catastrophe — myocardial infarction, stroke or sudden cardiac death. Techniques reviewed included global risk factor algorithms such as those based on the Framingham study (Sidney Smith, Chief Scientific Officer, American Heart Association, Dallas, USA), the use of ultrasound to estimate arterial-wall thickness (Olli Raitakari, Senior Lecturer, University of Turku, Turku, Finland), the use of computed tomography scanning with and without contrast to detect coronary calcification and/or define coronary stenoses, and the use of magnetic resonance imaging to outline areas of myocardial damage and even plaque characteristics. Steven Nissen (Vice Chairman, Cardiovascular Division, Cleveland Clinic, Cleveland, USA) presented exciting new data on the reversibility of atherosclerosis with aggressive cholesterol lowering. New intravascular ultrasound studies have shown that coronary plaques can undergo regression and stabilisation, potentially translating into clinical benefit for people with coronary artery disease. InterventionA major focus of interventional cardiology was the exciting results of trials using drug-eluting stent technology. Substudies from the RAVEL trial2 and smaller pilot registries suggest that sirolimus, a macrolide antibiotic with powerful antiproliferative properties, effectively prevents restenosis de novo not only in coronary lesions and femoral artery lesions but also with in-stent restenosis. Patients with diabetes seem to benefit to the same extent as those without diabetes. Promising data were also reported for stents eluting paclitaxel, while ongoing clinical trials are evaluating other drugs. ArrhythmiasThe highlight of the sessions on arrhythmias was the presentation by Bernard Gersh (Professor of Medicine, Mayo Clinic, Rochester, USA) of data from the AFFIRM study, in which 4060 patients with recent paroxysmal or chronic atrial fibrillation were randomly allocated to either a "rate control" arm (with emphasis on obtaining an acceptable ventricular response rate) or a "rhythm control" arm (with antiarrhythmic drugs and elective cardioversion to attain and maintain sinus rhythm). The primary outcome measure of the study was total mortality: there were 306 deaths in the rate control group, compared with 356 deaths in the rhythm control group (P = 0.056). For other endpoints, such as hospitalisation, ischaemic stroke and arrhythmia attributable to antiarrhythmic drugs, the rate control group also tended to do better. Nearly all strokes occurred in patients who had an international normalised ratio of less than 2.0 or who were not taking warfarin, emphasising the importance of anticoagulation therapy regardless of the treatment strategy. The general conclusion of this landmark study is that decisions on returning patients to sinus rhythm with aggressive antiarrhythmic therapies can be based largely on symptoms and patient preferences rather than the (incorrect) assumption that this approach will improve prognosis. Heart failureHeart failure remains the leading cause of medical admission in people over 65 years, and its prevalence is increasing as the population ages. The high level of morbidity associated with heart failure was illustrated by Duc and colleagues,3 who found that major depression is present in 18% of patients who have heart failure, and depressive symptoms in another 26%. These conditions are often unrecognised and untreated. The emerging role of B-type natriuretic peptide (BNP) in heart failure management was highlighted in the sessions. Post and colleagues4 reported that measuring BNP can help to distinguish cardiac causes of dyspnoea from non-cardiac causes in the emergency department. Mean levels of BNP were 83 pg/mL in patients with non-cardiac-related dyspnoea and 905 pg/mL in patients with heart failure. Aronson et al5 showed that administration of BNP increased heart rate variability, a surrogate for improved prognosis (heart rate variability is an indicator of autonomic function, low variability being associated with dysfunction and adverse prognosis). Carvedilol can be successfully initiated and titrated, and withdrawal rates have been low, even in high-risk groups such as elderly people6 and those with severe heart failure.7 Krum et al (in the COPERNICUS study)7 showed that within the first eight weeks of therapy there was no excess of clinical events, and death in high-risk groups was less for carvedilol than placebo (3 v 15 deaths; P = 0.005). The efficacy of biventricular pacing to achieve ventricular resynchronisation also received attention: the MIRACLE study8 of patients with moderately severe heart failure and wide QRS interval (> 130 msec) showed improved functional status, quality of life and exercise tolerance after this treatment. While "high tech" approaches to heart failure were featured in some presentations, a Spanish study showed that patient education through home visits, telephone contact and clinic review could halve the number of readmissions for heart failure.9 Other studies of home-based education also reinforced this finding, with Stewart et al, in a four-year follow-up study,10 demonstrating benefits in terms of reduced mortality and cost savings from reduced readmission. Acute coronary syndromesLars Wallentin (Director of Cardiology, Uppsala University Hospital, Uppsala, Sweden) presented late results from the FRISC2 study, which had shown the benefit of early revascularisation (by either angioplasty or bypass surgery) in patients with unstable angina or a small infarction. Benefit was maintained at two years, with death or infarction reduced from 16.3% to 12.1%. He speculated that these results will lead to increased intervention for acute coronary syndromes, but noted that the cost–benefit ratio could be maximised by selecting patients at increased risk based on clinical predictors. Despite the recent development of more powerful thrombolytic drugs than tissue plasminogen activator (tPA), initial studies showed no clinical benefit and possibly increased haemorrhage. It appears the thrombolytic ceiling has been reached, and this is probably also true of combinations of tPA with antithrombotic drugs. The one-year results of the GUSTO V study of abciximab plus tPA treatment for patients with ST-elevation infarction showed no reduction in mortality. This was similar to the 30-day findings in the same study (Michael Lincoff, Associate Professor of Medicine, Cleveland Clinic Foundation, Cleveland, USA). Thus, the significant early reduction in recurrent infarction and rescue angioplasty with abciximab did not translate into reduced late mortality. The most promising strategies for ST-elevation infarction involve prehospital fibrinolysis and early direct angioplasty. The latter strategy was investigated in a national study in Denmark (DANAMI-II), whose one-year results were presented by Henning Andersen (Professor of Cardiology, Skejby University Hospital, Aarhus, Denmark). There was reduced death and reinfarction in patients having angioplasty compared with those treated with thrombolytic agents, even though many were transported long distances by ambulance to the hospital performing the angioplasty. Most of the benefit was in reduced reinfarction, a result that may also be achievable with lytic therapy plus low molecular weight heparin, together with elective revascularisation in the first few days after infarction. Molecular biology In a plenary session on gene and cell therapy, speakers highlighted the potential and possible limitations of a molecular biology approach for end-stage heart disease. Genes to promote angiogenesis have been used in early clinical trials of patients with severe coronary and peripheral vascular disease, with some promising results summarised by Elizabeth Nabel (Director, Clinical Research Program, National Heart, Lung, and Blood Institute, Bethesda, USA). The next phase was to use endothelial progenitor cells to assist in the cellular component of the response. Early data on the possible benefit of muscle stem-cell therapy for severe heart failure were presented by French11 and Dutch12 investigators. There was some concern that skeletal myoblasts may contribute to arrhythmogenesis. The winner of the International and CSANZ Young Investigator Basic Science Award, Thomas Yeoh (Research Fellow, Victor Chang Institute, Sydney), presented data on the control mechanisms of proliferation of skeletal muscle stem cells. This area of research is receiving intense interest internationally. In a provocative presentation entitled "Bench to bedside", Claude Lenfant (Director, National Heart, Lung, and Blood Institute, Bethesda, USA) stressed the need for translating the discoveries in the basic sciences into clinical care. In other sessions, Christine Seidman (Professor of Medicine and Genetics, Harvard Medical School, Boston, USA) showed how understanding gene defects and the changes they produce in myocardial proteins is unlocking the mechanism of an increasing number of cardiomyopathies underlying heart failure. Highlights of the 14th World Congress of Cardiology* Worldwide issues Epidemic of cardiovascular disease in developing countries Tobacco, diabetes and obesity Global cardiovascular risk assessment Atherosclerosis Inflammation Presymptomatic detection of coronary artery disease Reversibility with aggressive cholesterol reduction Intervention Drug-eluting stents Arrhythmia Rate or rhythm control for atrial fibrillation Heart failure B-type natriuretic peptide Beta-blockers Outpatient management Acute coronary syndromes Acute intervention New fibrinolytics and antithrombotics Molecular biology Gene and cell therapy Genes and cardiomyopathy * Some of the highlights are available as a webcast on <http://www.prous.com/wcc2002/program.asp#> (accessed 8 September 2002, no longer available).

Saul B Freedman PhD, FRACP

The benefits of statin therapy do not come without financial cost The aim of the recently reported Heart Protection Study1 in the United Kingdom, with over 20 000 participants aged 40–80 years, was to establish whether statin therapy is of benefit to people who are at high risk of cardiovascular disease (CVD) but have average-to-low levels of total cholesterol and LDL-cholesterol. High-risk patients (defined as those having previous coronary heart disease, diabetes, stroke, or peripheral vascular disease) were treated with simvastatin (40 mg daily), antioxidant vitamins (20 mg beta-carotene, 250 mg vitamin C and 600 mg vitamin E daily) or placebo in a 2 × 2 factorial design. Among patients allocated to the antioxidant arm of the trial, there was no change in incidence of any prespecified endpoints, and there were small but significant increases in blood levels of LDL-cholesterol and triglycerides, which have the potential to increase CVD risk with long-term antioxidant use.2 High-dose antioxidant therapy is therefore not recommended.3 Reductions in cardiovascular events (including myocardial infarction, stroke and either coronary or peripheral arterial revascularisation) occurred with simvastatin therapy in women, elderly people, and people with previous cerebrovascular disease, peripheral artery disease, renal impairment or diabetes (see Box). Translating the results of the HPS into clinical practice, patients with an absolute overall CVD risk of more than 17% over five years (the lowest rate occurring in any subgroup of the HPS treated with placebo) should receive high-dose statin therapy, equivalent to 40 mg/day simvastatin, independent of baseline levels of total cholesterol; and other cardioprotective therapy, such as β-blockers and aspirin. Overall CVD risk can be estimated with the National Prescribing Service charts,4 which refer to CVD rather than coronary heart disease risk — a strategy flowing from the HPS outcomes.1,4 These charts, based on the Framingham study, provide only an approximation of absolute risk, but serve as a useful guide. Examples of patients with five-year CVD risk above 17% include most men over 60 years who smoke and have diabetes, and a 60-year-old non-smoking, non-diabetic man with blood pressure of 160/95 mmHg and a total cholesterol/HDL-cholesterol ratio of 6: 1.4 Benefits are likely to occur after 12 months of statin therapy, with greater benefits occurring the longer therapy is continued. Allowing for non-compliance, the HPS showed that about a third of major CVD events are likely to be prevented by statin therapy over five years. In the HPS, 23% of patients in the simvastatin group were smokers, 22% were being treated with antihypertensive agents, 20% with β-blockers, 25% with angiotensin-converting enzyme inhibitors (ACE inhibitors) and 21% with aspirin. Relative risk reductions in CVD incidence of up to 80% may be expected when statins are combined with standard cardioprotective agents (aspirin, β-blockers and ACE inhibitors) and stopping smoking.3 Given that CVD reduction in the HPS was independent of baseline cholesterol levels, it has been suggested that lipid levels need not be measured before commencing statin therapy in high-risk patients.3 However, fasting levels of triglycerides and HDL-cholesterol should be measured after 1–2 months, as therapy may need to be modified if these lipids are inadequately controlled by statin therapy alone. For example, gemfibrozil therapy may be considered for patients with low HDL-cholesterol levels.5 The HPS included about 6000 individuals with diabetes — the largest number in any statin trial reported to date. The CVD event rate for placebo-treated diabetics without coronary heart disease was 18.6%, compared with 22.5% for non-diabetics with coronary heart disease. Thus, the HPS confirms diabetes as a "coronary-equivalent" risk disorder for CVD.6 However, risk of CVD may vary from low to very high, depending on age and other risk factors, so it is still necessary to determine the global risk of CVD for an individual with diabetes when assessing the need to treat with a statin.4 Subjects at highest risk of CVD in the HPS had slightly elevated baseline serum creatinine levels (> 200 μmol/L), although only results of univariate analysis have been provided. The HPS confirms the high CVD risk in patients with impaired renal function and also supports the need for treatment of their dyslipidaemia.7 Caution is required in giving statin therapy to patients with more severe renal impairment, as they are at increased risk of myopathy.8 In the HPS, the safety profiles for statin and placebo therapy were similar. This finding may partly be a consequence of the exclusion of patients who showed adverse reactions to simvastatin during a 4–6-week run-in period leading up to the trial. However, only 32% of 63 603 screened patients were allocated to receive simvastatin in the study, so the low adverse event rate in the study may not necessarily apply to an unselected population. Of particular importance with regard to safety was the low incidence of myopathy (defined as serum creatine kinase levels exceeding 10 times the upper limit of normal), which occurred in only 11 simvastatin-treated patients and six placebo-treated patients. These results are reassuring, but muscle symptoms and creatine kinase levels should still be monitored periodically, and withdrawal of statin therapy should be considered if myalgia occurs or creatine kinase levels rise to more than three times the upper limit of normal.9 There were no apparent safety concerns in patients with low baseline LDL-cholesterol levels (< 3 mmol/L), in whom average LDL-cholesterol levels during the trial were 1.8 mmol/L in the simvastatin-treated group and 2.7 mmol/L in the group receiving placebo. The association between low levels of total cholesterol and increased cerebral haemorrhage found in a study by Iso et al10 was not borne out by the HPS. The safety and efficacy of treatment with 40 mg/day of simvastatin demonstrated by the HPS will probably result in a higher average dose being used in Australia, where the current average dose is 25 mg/day (Glen Godresse, Specialist/Hospital Product Manager, Merck Sharp and Dohme Australia Pty Ltd, personal communication). The benefits of statin therapy do not come without financial cost, although the long-term savings as a result of statin therapy are very likely to outweigh that cost.11 As CVD remains the single most important cause of mortality in Australia, consideration should be given to extending the availability of statins under the Pharmaceutical Benefits Scheme to include patients shown in the HPS to benefit from therapy: diabetics, women over 40 years, elderly people, and those with peripheral vascular disease, renal disease and low-to-average cholesterol levels, if their estimated global CVD risk exceeds 17% over five years.4 Absolute risk reductions and numbers needed to treat to prevent one cardiovascular event1 Event ARR (%)* NNT† All-cause mortality 1.8% 56 Mortality due to CHD 1.5% 83 Non-fatal myocardial infarction 2.1% 48 Coronary revascularisation 2.6% 38 Ischaemic stroke 1.2% 83 MVE without baseline CHD 4.7% 21 MVE with baseline CHD 5.7% 18 MVE with baseline creatinine > 200μmol/L 9.0% 11 MVE in patient aged < 65 years 5.2% 19 MVE in patient aged ≥ 70 years 5.1% 20 CHD = coronary heart disease. MVE = major vascular event (includes CHD, stroke, revascularisation). * Absolute risk reduction (%), simvastatin therapy v placebo. † Number needed to treat with simvastatin 40 mg/day to prevent one event over 5.3 years.

Ian Hamilton-Craig PhD FRACP

Objective: To measure the cost-effectiveness of cholesterol-lowering therapy with pravastatin in patients with established ischaemic heart disease and average baseline cholesterol levels.Design: Prospective economic evaluation within a double-blind randomised trial (Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID]), in which patients with a history of unstable angina or previous myocardial infarction were randomised to receive 40 mg of pravastatin daily or matching placebo.Patients and setting: 9014 patients aged 35–75 years from 85 centres in Australia and New Zealand, recruited from June 1990 to December 1992.Main outcome measures: Cost per death averted, cost per life-year gained, and cost per quality-adjusted life-year gained, calculated from measures of hospitalisations, medication use, outpatient visits, and quality of life.Results: The LIPID trial showed a 22% relative reduction in all-cause mortality (P < 0.001). Over a mean follow-up of 6 years, hospital admissions for coronary heart disease and coronary revascularisation were reduced by about 20%. Over this period, pravastatin cost $A4913 per patient, but reduced total hospitalisation costs by $A1385 per patient and other long-term medication costs by $A360 per patient. In a subsample of patients, average quality of life was 0.98 (where 0 = dead and 1 = normal good health); the treatment groups were not significantly different. The absolute reduction in all-cause mortality was 3.0% (95% CI, 1.6%–4.4%), and the incremental cost was $3246 per patient, resulting in a cost per life saved of $107 730 (95% CI, $68 626–$209 881) within the study period. Extrapolating long-term survival from the placebo group, the undiscounted cost per life-year saved was $7695 (and $10 938 with costs and life-years discounted at an annual rate of 5%).Conclusions: Pravastatin therapy for patients with a history of myocardial infarction or unstable angina and average cholesterol levels reduces all-cause mortality and appears cost effective compared with accepted treatments in high-income countries.

Paul P Glasziou FRACGP, PhD · Simon D Eckermann BEc(Hons), BSc(Ma · Sarah E Mulray BA · R John Simes FRACP, MD · Andrew J Martin MA, PhD · Adrienne C Kirby BSc(Hons), MSc · Susan Caleo BPharm, GradDipSci · Jane P Hall BA, PhD · Harvey D White DSc, FRACP · Andrew M Tonkin MD, FRACP

Benefits depend on the patient’s absolute cardiovascular and bleeding risks The benefit of aspirin for patients with previous symptomatic atherothrombosis of the heart, brain and limb in the secondary prevention of recurrent serious vascular events is well established. However, the role of aspirin in the primary prevention of cardiovascular disease among people who have no symptoms of vascular disease is controversial.1 A recent summary of the evidence has prompted recommendations from the third US Preventive Services Task Force2,3 and the American Heart Association.4 The evidence is based on a systematic review of five randomised controlled clinical trials of the effectiveness and safety of long-term aspirin use (75–500 mg a day or every other day) over 3–7 years in over 50 000 individuals with no previous symptomatic cardiovascular disease.5-9 Most participants were middle-aged men, although there were more than 10 000 women included in two trials and substantial numbers of patients aged 70–80 years in four of the five trials. Among patients randomly allocated to receive aspirin, the rate of subsequent serious vascular events (non-fatal stroke, non-fatal myocardial infarction, or death due to vascular causes) was reduced significantly, from 4.8% (no aspirin) to 4.2% (aspirin) over about 56 months' follow-up. This is an odds reduction of 13% (95% CI, 5%–19%) and an annual risk reduction of about 0.1% (ie, one serious vascular event avoided per 1000 patients treated with aspirin for one year) (see Box). Most of the benefits of aspirin were due to a significant 28% (95% CI, 13%–40%) reduction in the odds of a coronary event (myocardial infarction or sudden death). There was no reduction in the occurrence of all stroke. However, aspirin was associated with a non-significant 40% (95% CI, −10% to 100%) increase in the odds of haemorrhagic stroke, which is consistent with the excess risk of haemorrhagic stroke seen in secondary prevention trials using aspirin.1 In absolute terms, this represents an excess risk of one haemorrhagic stroke per 10 000 patients treated with aspirin per year.10 Aspirin was also associated with a 70% (95% CI, 40%–110%) increase in the odds of major extracranial (mainly gastrointestinal) haemorrhage, which is an excess of 0.7 (95% CI, 0.4–0.9) major extracranial haemorrhages per 1000 patients treated with aspirin per year (see Box).10 The Preventive Services Task Force concluded that there is now good evidence that aspirin lowers the incidence of coronary heart disease (CHD) in adults who are at increased risk, and that it also increases the incidence of gastrointestinal bleeding.2 It considered that there was fair evidence that aspirin increases the risk of haemorrhagic stroke.2 The evidence was most reliable for men aged 40–75 years and less reliable for women and older men. The optimum dose of aspirin is not known, but dosages of 75–150 mg/day seem to be as effective as higher doses and are associated with a lower risk of adverse gastrointestinal effects. The American Heart Association recommends low-dose aspirin prophylaxis in people with a 10-year CHD risk of over 10% (ie, > 1% per year),4 whereas the Preventive Services Task Force recommends aspirin for people with a five-year CHD risk of over 3% (ie, > 0.6% per year).2,3 The latter is justifiable, in our view: for every 1000 patients with a 3% risk of a coronary event over five years, long-term aspirin therapy prevented 4–12 coronary events and caused 0–2 haemorrhagic strokes and 2–4 major gastrointestinal bleeding events. This represents a benefit-to-harm ratio of about 2.0 (see Box). The benefit-to-harm ratio of aspirin was most favourable among people at high risk of a future cardiovascular event and low risk of haemorrhagic complications. The implication for clinicians is that decisions to prescribe aspirin therapy for the primary prevention of cardiovascular events should be based on an assessment of the patient's absolute risk of a vascular event without aspirin, the absolute risk of a gastrointestinal or intracranial haemorrhage with aspirin, and the patient's preference. In addition, decisions about aspirin therapy should be reviewed at least every five years, or when new vascular risk factors are detected. Risk stratification should incorporate specific information about multiple risk factors, rather than simply counting the number of risk factors.11,12 Risk factors for cardiovascular disease include increasing age, being male, cigarette smoking, increasing blood pressure, increasing blood total cholesterol level, decreasing high-density lipoprotein cholesterol level, raised fasting blood glucose level (ie, diabetes mellitus), and a positive family history of cardiovascular disease (in younger adults).4,13 Risk factors for haemorrhagic complications of aspirin include increasing age, any bleeding diathesis, uncontrolled hypertension, and concomitant use of other nonsteroidal anti-inflammatory agents or anticoagulants. Enteric-coated or buffered preparations of aspirin do not clearly reduce adverse gastrointestinal effects. People at increased cardiovascular risk who may wish to consider long-term aspirin therapy (75–150 mg/day) are men over 40 years of age, postmenopausal women, and younger people with risk factors for cardiovascular disease (eg, hypertension, diabetes).4,13 However, there is still insufficient information to reliably identify the minority of individuals who will benefit and the minority who will be harmed by regular treatment with aspirin. Further information will soon be available from several studies: the Women's Health Study (comparing aspirin 100 mg taken every alternate day with placebo among 40 000 healthy postmenopausal women); the Aspirin in Asymptomatic Atherosclerosis trial (comparing low-dose aspirin with placebo in 3300 middle-aged participants with asymptomatic peripheral atherosclerosis, identified by an ankle brachial pressure index of ≤ 0.9); and the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trial (comparing aspirin with a clopidogrel/aspirin combination for preventing serious vascular events among about 15 000 people at high risk of cardiovascular disease who are currently taking aspirin). In the meantime, the challenge for clinicians is to translate the evidence into practice by ascertaining the absolute risk of subsequent serious vascular events for all people who may be at risk, and to prescribe long-term aspirin 75–150 mg/day, with long-term follow-up, for those with an absolute risk of CHD exceeding 3% over the next five years. The challenge for academic clinicians is to devise more valid "risk calculators" that incorporate the risk of serious cardiovascular events and the risk of adverse events, such as intracranial and gastrointestinal haemorrhage. Summary (based on five randomised controlled trials) of the effectiveness of long-term aspirin use in primary prevention of coronary events3 Absolute risk (%) Number of events avoided or caused (95% CI)* Outcomes Control Aspirin Odds ratio (95% CI) AR 1% AR 3% AR 5% Benefits (events avoided) All coronary events (non-fatal or fatal MI, or sudden death) 2.4% 1.9% 0.72 (0.60–0.87) 3 (1–4) 8 (4–12) 14 (6–20) Fatal coronary events 0.7% 0.6% 0.87 (0.70–1.09) All-cause mortality 3.5% 3.4% 0.93 (0.84–1.02) 1 (0–2) 2 (0–5) 4 (0–8) Non-fatal stroke, non-fatal MI, or death due to vascular causes 4.8% 4.2% 0.87 (0.81–0.95) 1 (0–2) 4 (2–6) 6 (2–10) No change All stroke 1.3% 1.4% 1.02 (0.85–1.23) NC NC NC Harms (events caused) Haemorrhagic stroke† 0.17% 0.22% 1.4 (0.9–2.0) 1 (0–2) 1 (0–2) 1 (0–2) Major gastrointestinal bleeding event‡ 0.5% 0.8% 1.7 (1.4–2.1) 3 (2–4) 3 (2–4) 3 (2–4) Benefit-to-harm ratio 0.75 2.0 3.5 MI = myocardial infarction. NC = no change. * Events per 1000 patients treated for five years with aspirin, compared with no aspirin, according to the patient's baseline absolute risk (AR) of coronary heart disease over the next five years. † Data from secondary prevention trials suggest that increases in haemorrhagic stroke may be offset by reduction in ischaemic stroke in patients at very high risk for cardiovascular disease (ie, > 10% risk over five years). ‡ Rates may be two to three times higher in people aged over 70 years.

Graeme J Hankey MD FRCP FRACP · John W Eikelboom MSc FRACP FRCPA

In reply: Aroney's letter raises a number of important issues. The first of these is the question of whether a scientific fact requires the blessing of peer review to become established as such. The corollary of this is whether or not all peer-reviewed facts are necessarily true. The answer to both questions is probably no. The second issue is how to control a media report, irrespective of whether it is based on a peer-reviewed study. The issue which concerns Aroney is an abstract presentation of the association of gastrointestinal bleeding with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase II (COX-II) inhibitors, the conclusion of which was that, while the last two might be important in their own right, concurrent use of aspirin, even in a small dose, was more closely associated with bleeding risk, particularly if there was a past history of peptic ulceration.1 A "meta-analysis" of the media reports, which included both television and radio in addition to the quoted report in the Sydney Morning Herald,2 would have made it clear that the theme of the interviews reaffirmed the relative safety of aspirin in the vast majority of individuals, and highlighted the risk of aspirin use concurrently with NSAIDs and COX-II inhibitors, particularly when there is a history of past ulceration. The fact that the SMH report focused on one aspect of the study was counterbalanced by the others. We do not know how journalistic reporting is controlled. A primary question is whether or not aspirin is an effective agent for the prevention of cardiovascular disease beyond the management of acute myocardial infarction. More recent literature than that quoted by Aroney is now questioning the overall cardioprotective value of aspirin.3 This showed that aspirin given as prophylaxis against cardiovascular disease increased the risk of sudden death in every secondary prevention study and left the overall rate of myocardial infarction unchanged.4 Aspirin consistently failed to reduce overall mortality in every study of long-term prophylaxis after myocardial infarction, and in all but one after stroke.3 Furthermore, Cleland and colleagues have argued that a series of meta-analyses, which most people have accepted as proof of the efficacy of aspirin, are of doubtful validity.4 They questioned whether it is appropriate for the medical community to invest so much time and effort in prescribing aspirin and dealing with the adverse consequences of its long-term ingestion to the neglect of other, better proven and apparently more effective therapies such as angiotensin-converting enzyme inhibitors, β-blockers, and statins. At the very least, it can be said that there is controversy in the cardiovascular literature about the benefits of aspirin. Just as important is the issue of the safety of long-term aspirin use for cardioprotection. A recent multidisciplinary expert statement on NSAIDs concluded that, on current evidence, prophylactic use of aspirin should be reserved for patients with established vascular disease, because in other patients bleeding risks may outweigh cardiovascular benefit.5 A Danish study showed that 100–150 mg of aspirin daily increased the risk of haematemesis by a factor of 2.6, with no difference in the risk between enteric and non-coated product; when combined with an NSAID the risk was increased by a factor of 5.6.6 The authors concluded that the bleeding risk may offset some of the benefits of aspirin. It is no longer appropriate to simply "bury" the adverse gastrointestinal effects of low-dose aspirin in the NSAID side-effect "basket".7 It is apparent to us that dogma should not be so enshrined that it prevents the discussion of issues that might helpfully modify that dogma.

Terry D Bolin · James V Bertouch MD

In reply: The letter from Aroney displays some basic misunderstandings of the role of the media in reporting medical issues. Aroney states that "the press [has] a responsibility . . . to avoid recommendations which are not evidence-based and which detract from our efforts to reduce mortality from . . . cardiovascular disease." A press article does not itself make recommendations when it reports the recommendations of others — an essential distinction. In addition, the press has no responsibility to follow the agenda of the medical profession and its slavish insistence on the dogma of evidence-based medicine. The press owes doctors no more favours than it owes any other sector of the community. The role of the press is to raise and debate issues of public interest in a manner that is balanced and responsible. The news report about aspirin did all of this.1 We agree that publication in a peer-reviewed journal may add scientific credibility to research findings and that this may sometimes make them more newsworthy. But our responsibility is to report medical matters of interest to the community, which means we are not limited to peer-reviewed findings. Any substantial fact, observation or opinion relating to medical practice is fair game for a newspaper's attention. After the findings of Bertouch and colleagues were presented at a conference,2 they entered the public domain, as did their later comments made to us directly. It was entirely proper to report them. The fact that the gastrointestinal bleeding study was conducted by two heads of department at a major Sydney teaching hospital was instrumental to our decision to position and headline the report prominently. These individuals are respected experts in their fields, and they expressed to us serious concern about the degree to which aspirin was implicated in gut haemorrhage. It was that concern which led us to focus on the aspirin findings within the broader study. The news process is always selective and there is no obligation to give equal emphasis to all findings. The magnitude of follow-up by other media confirms the inherent public interest in the topic. It has previously been suggested that medical journalists are behaving irresponsibly when they step outside the strictures of peer review.3,4 Yet it is a basic tenet of journalistic ethics that journalists should be independent.5 Why, then, would we subscribe to the doctrine of evidence-based medicine, with all its flaws? We, and the community, have every right to be sceptical of the tyranny of peer review when the pharmaceutical industry manifestly uses financial muscle to influence what is studied and what is published.6 Even the Medical Journal of Australia accepts anecdotal findings when it can persuade itself the public interest is involved, recently publishing an eyewitness account of conditions inside an immigration detention centre7 and defending this on the basis that "our readership is sophisticated enough to interpret the content of such articles."8 Sydney Morning Herald readers are also sophisticated. On what basis should they have been denied this pertinent information about a widely used medicine — that doctor still knows best?

Julie Robotham BA(Oxon) · Robert Whitehead

Objectives: To determine (i) factors which predict whether patients hospitalised with acute myocardial infarction (AMI) receive care discordant with recommendations of clinical practice guidelines; and (ii) whether such discordant care results in worse outcomes compared with receiving guideline-concordant care.Design: Retrospective cohort study.Setting: Two community general hospitals.Participants: 607 consecutive patients admitted with AMI between July 1997 and December 2000.Main outcome measures: Clinical predictors of discordant care; crude and risk-adjusted rates of inhospital mortality and reinfarction, and mean length of hospital stay.Results: At least one treatment recommendation for AMI was applicable for 602 of the 607 patients. Of these patients, 411(68%) received concordant care, and 191 (32%) discordant care. Positive predictors at presentation of discordant care were age > 65 years (odds ratio [OR], 2.5; 95% CI, 1.7–3.6), silent infarction (OR, 2.7; 95% CI, 1.6–4.6), anterior infarction (OR, 2.5; 95% CI, 1.7–3.8), a history of heart failure (OR, 6.3; 95% CI, 3.7–10.7), chronic atrial fibrillation (OR, 3.2; 95% CI, 1.5–6.4); and heart rate ≥ 100 beats/min (OR, 2.1; 95% CI, 1.4–3.1). Death occurred in 12.0% (23/191) of discordant-care patients versus 4.6% (19/411) of concordant-care patients (adjusted OR, 2.42; 95% CI, 1.22–4.82). Mortality was inversely related to the level of guideline concordance (P = 0.03). Reinfarction rates also tended to be higher in the discordant-care group (4.2% v 1.7%; adjusted OR, 2.5; 95% CI, 0.90–7.1).Conclusions: Certain clinical features at presentation predict a higher likelihood of guideline-discordant care in patients presenting with AMI. Such care appears to increase the risk of inhospital death.

Ian A Scott FRACP, MHA · Catherine M Harper BSc, MPHTM

Three articles in the Christmas issue of the Journal,1-3 responding to media coverage of a proposed clinical trial,4 failed to address the objections raised to conducting the trial without patient consent. The proposed trial, the Royal North Shore (RNSH) and Ambulance Regional Study of a Stenting Strategy as an Alternative to Lytic/Medical Therapy in Acute Myocardial Infarction (RARE SALAMI), was to be conducted in Sydney's Northern Area Health Service. The aim was to compare two regimens of management of patients with acute myocardial infarction and determine whether, despite some additional transit time, diverting ambulances past local hospitals (where patients would receive thrombolytic treatment) and on to the services at RNSH (where patients would be treated with percutaneous coronary intervention) would be beneficial to patients (Box 1).1 The trial would involve the ambulance service, RNSH and the emergency departments of four district hospitals within the health area. Senior medical staff from two of the emergency departments were among those who expressed concerns in the media reports.4 Diversions from standard treatmentInherent in the trial were a number of diversions from standard treatment and procedures. These included contravening the standard advice provided to the community regarding emergency cardiac care — to attend the nearest hospital emergency department as quickly as possible; interference in established therapeutic networks and ongoing therapeutic relationships, including relationships with hospitals; and, most importantly, delays in time to treatment. Delays in time to treatment were to be caused by: Performing a resting 12-lead electrocardiogram (ECG) at the point of ambulance pick-up of patients with cardiac symptoms for the purpose of the selection and allocation of trial subjects; Informing the allocating person at the ambulance control centre of the computer report of the ECG and awaiting randomisation; Transport of subjects randomised to the experimental group past hospitals with facilities for thrombolytic treatment and a private tertiary hospital providing acute invasive cardiac procedures, thereby adding up to about 40 km of suburban roads to the emergency dash. Adding uncontrolled clinical variables (eg, intercurrent illnesses) and location difficulties caused by heavy traffic at peak periods, a lift bridge and intermittent road closures due to environmental hazards (eg, low-level flooding, bushfires). Opposition to the trialIt was evident from all the MJA articles that many people within the profession and in the community opposed the trial. There are several reasons for this opposition, including: local geographical issues of transport and the present distribution of health services; issues of risk and inconvenience for patients; methodological issues such as experimental design, rationale and execution of the trial; and no provision for meaningful consent before entry into the trial.1-4 Despite this opposition, at the time of the media investigation the trial was about to be implemented. Members of the community and hospital and ambulance staff not wanting to be involved in the trial were about to be included. Indeed, in the period between the media reports and the Christmas issue of the MJA, one metropolitan council included in the trial area formally documented its view in relation to the proposed trial and conveyed this to the relevant ethics committee.5 The following motion was carried unanimously: Council opposes the conducting of medical trials on any member of the community without their full informed consent — this particularly applies in the treatment of cardiac conditions. Patient consentIn the MJA articles it was proposed that "ethics committees (can) assume the responsibility of giving consent on behalf of patients",1 and that, "almost by definition, people in the midst of life-threatening medical emergencies, who may be unconscious, in shock, in extreme pain or delirious, surrender their normal sentient ability to consent".2 However, this denies one of the cornerstones of medical ethics — the patient's right to self-determination. This is not to say that clinical trials should be discarded. Experimenting on patients, often in the form of a clinical trial, is an essential element of evaluating drugs and therapeutic innovations. Patients are patients because they present for and need treatment. They are entitled to a treatment that is tried and true — in this case, standard rescue protocols for myocardial infarction — and, unless otherwise indicated, they must reasonably trust that that is what they are getting. Accordingly, medical staff and, in this case, ambulance personnel are obliged to provide such care. Service organisations and clinician-researchers may experience tension between their obligation to provide a certain type of treatment and the need to divert from accepted standards for research purposes. Fortunately, there are guidelines to ease this tension and to chart the correct course of action. The Nuremberg Code of 19476 is the modern forerunner of these guidelines. It has the appeal of being a simple 10-point code and, until 1964, when the World Medical Association (WMO) produced its first set of guidelines (the Declaration of Helsinki), was the only code of its kind. Subsequently, there have been revisions of the WMO's Declaration7 and the development of various national codes, including the Australian National Health and Medical Research Council (NHMRC) statement on research involving humans. The NHMRC's 1999 National Statement8 is currently the primary guide to clinical research in Australia. As with other guides, it emphasises the importance of fully informed consent and sets out the circumstances in which patients can be included in clinical trials without their knowledge or consent. Criteria for proceeding without consentConsent is reviewed in considerable detail in the NHMRC Statement on Ethical Conduct in Research Involving Humans.8 Statements relating to areas where consent is either waived or considered not necessary appear in paragraphs 1.11, 6.9, 14.4, 15.8, 16.13 and 17.1 and 17.2. Paragraphs 14.4, 15.8 and 16.13 relate to identifiable data, tissue samples and genetic issues. Interestingly, even in survey-type activities where consent is not required, Part 17 ensures there should be no element of deception. Part 6 considers emergencies, intensive care, terminal care, those with impaired capacity for communication, those highly dependent on care, and the unconscious (see summary in Box 2). In relation to emergency situations, the vulnerability of patients and relatives is acknowledged, as is the inability to obtain consent. When research may produce a ". . . reduction of potential benefits", Part 6.9 gives specific guidance, stating that the research should not be contrary to the patient's interests; must be based on valid scientific hypotheses; must ensure that the patient/relatives are able to give consent or withdraw the patient from the research as soon as reasonably possible; and, most importantly, must ensure that there is no increased risk to the individual. Leeway has been allowed for proceeding with experimental techniques without consent when a number of the conditions are met. The essence of these can be summarised as follows: The choice is between essentially no treatment and experimental treatment; The experimental treatment offers the chance of benefit and no greater harm; and There are reasonable grounds for assuming that the patient would consent if he or she were able to. Similar leeway has been allowed by the Food and Drug Administration (FDA) in the United States. The FDA undertook review of this area in response to concerns expressed by researchers that ". . . current rules are making high quality acute care research difficult or impossible to carry out when the need for such research is increasingly recognized". As a result, regulation 50.24 became effective in 1996.9 These guidelines are summarised in Box 3. While institutional ethics committees may interpret the FDA guidelines differently for specific treatments,10 the circumstances that allow waiver of consent in emergency situations are similar to those outlined by the NHMRC. They include proceeding with acute resuscitation that is experimental at the time of a cardiac arrest when standard treatment has failed; trialling the acute use of a neuroprotective agent when a patient arrives in the emergency department in a deeply comatose state; or, as recently reported, the administration of standard anticonvulsants by ambulance personnel.11 Will patients be harmed?The downside of any clinical experiment is that the hypotheses may turn out to be wrong and patients may be harmed. The RARE SALAMI trial requires delaying accepted efficacious cardiac treatment in emergency situations in which there is a very high mortality rate in the first hours. The hypothesis that no harm will be done to the patients is put forward in one of the articles as a foregone conclusion,1 but doctors with a working knowledge of local practicalities of the catchment area were clearly not convinced by these arguments,4 and neither were the intended research subjects, their representatives and statutory authorities, who were moved to formalise concerns.1,5 Such situations are succinctly covered in the Nuremberg Code. Point 5 states: No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. ConclusionsKomesaroff is correct in stating that this imbroglio provides several important lessons about process.3 In addition, it is a reminder of the need to guard against confusing "consent to treatment" with "consent to research", and to avoid distorting what the guidelines say. This applies particularly to what the NHMRC National Statement says about consent for research in persons highly dependent on medical care. Finally, it is most important to remember what calling an ambulance is all about. With regard to consent, the trial cannot be imposed on an unwilling community and unwilling doctors. It should not proceed until the following conditions are met: 1. At the community level There is factual agreement between the researchers and the community as to the time delays involved; There is broad agreement within the profession as to the risk to patients; There is agreement between researchers and the local community, including local general practitioners and specialists, as to the disruptions that would be caused by the trial; Arrangements are in place to detect and make good any harms caused; and The community agrees that the benefits of the project to their community are worth the costs to the community. 2. At the level of individual research subjects All persons in the communities involved with the trial have been informed of the details of the proposal, including the risks and benefits to research subjects, by means of mailing and public meetings, and their comprehension of the information has been established by a survey; and There are provisions for opting out and confirmation of informed consent at the point of first contact by ambulance personnel. This is informed consent in action. Without it, some experiments simply cannot be done. 1: Proposed sequence of events for a trial to compare two regimens of management for acute myocardial infarction 2: Summary of National Health and Medical Research Council guidelines for research without consent Paragraph 1.7 If a participant lacks competence to consent, a person with lawful authority is provided with the information and exercises that choice. Paragraph 6.9 When conformity to the principle of consent (paragraph 1.7) is not feasible, and neither the participant nor the individual's representative can give consent in advance, a Human Research Ethics Committee may approve a research project without prior consent provided the proposal (a) is not contrary to the patient's interest; (b) does not place the patient at any more risk than that which is inherent in the patient's condition; (c) is based on a valid hypothesis; and (d) the patient, the patient's relatives and legal representatives will be informed as soon as possible and given the choice to continue the experiment or withdraw the patient. 3: Summary of FDA Guidelines for research without consent 1. Life-threatening situation, available treatments unproven or unsatisfactory and an experiment, including the use of placebo, is needed to answer the question. 2. Consent not feasible because (a) of the medical condition, (b) it must be administered before an authorised person can give consent, (c) it is not possible to identify subjects before the condition occurs. 3. Subjects may benefit because (a) they are in a life-threatening situation, (b) animal or preclinical studies show the potential for benefit, (c) the risks are reasonable allowing for what is known about the condition. 4. The study could not be conducted without a waiver. 5. The time window for the experimental intervention is defined and during this time the investigator is committed to finding the subject's duly authorised representative rather than proceeding without consent. 6. Community consultation before the study to explain risks and expected benefits. 7. Public disclosure of the results. 8. Independent monitoring of the results. 9. The subjects (or their representatives) are informed as soon as possible as to their inclusion in the study.

Michael C Kennedy MD, FRACP

Case report A 63-year-old woman with hypertension and non-insulin-dependent diabetes underwent restudy coronary angiography for recurrent angina. She had had coronary angioplasty in 1991 and coronary arterial bypass surgery in 1998 with two saphenous vein grafts and a left internal mammary artery graft. Angiography of her native coronary arteries, both saphenous vein grafts, and a left ventriculogram were completed without difficulty. The left internal mammary artery was more difficult to engage selectively. The left vertebral artery, which was adjacent, was outlined by contrast. During this time the patient's blood pressure increased to 200/110 mmHg and she became nauseous and vomited. She complained that "everything has gone black". The study was terminated with a non-selective injection into the left subclavian artery, which showed an adequate left internal mammary artery graft. A total of 160 mL of non-ionic, low-osmolar contrast agent ("Ultravist") containing iopromide was used. During post-procedure monitoring she could not see light or objects and complained of headache. There was impaired alertness. Her blood pressure stabilised at 140/80–160/90 mmHg. Her pupils were equal and reactive to light. Extraocular muscle movements were normal. Funduscopy revealed "copper wiring" of hypertension without significant diabetic retinopathy. Cranial nerve, peripheral motor and sensory examinations were normal. Bilateral cortical blindness was diagnosed. Computed tomography (CT) brain scan was performed three hours after the completion of coronary angiography. No additional contrast was used. The CT brain scan (Box 1) showed marked bilateral contrast enhancement of the occipital lobes and no evidence of a cerebral haemorrhage. Intravenous heparin treatment was commenced. By the following day, she was able to see shapes and shadows but had persistent headache and nausea. A repeat CT brain scan did not show any residual abnormality. During the next 48 hours, her vision progressively returned. She described flashing lights in her right eye and had evidence of right homonymous hemianopia. Magnetic resonance imaging (MRI) showed increased signals in the grey matter of the medial aspect of the left occipital lobe, on a background of longstanding mild ischaemic changes consistent with her age and cardiac risk factors (Box 2A). Magnetic resonance angiography (MRA) showed patency of both posterior cerebral arteries, with dilatation of branches supplying the left occipital lobe (Box 2B). Heparin therapy was ceased, as there was no evidence of acute thromboembolism or acute infarction. She fully regained her vision five days after coronary angiography. Transient cortical blindness related to coronary angiography was first reported in 1970.1 Since then there have been fewer than two dozen cases recorded, some of which include angiography of coronary bypass grafts.2-5 This is a rare neurological complication given the widespread and frequent use of such investigations worldwide. The incidence of cerebrovascular complications in diagnostic cardiac catheterisations and coronary angiography is low. The National Institutes of Health in America reported a rate of 0.03%,6 and the British Cardiac Society report from 34 041 patients gave an incidence of 0.06%.7 This included cerebrovascular accidents, transient ischaemic attacks and amaurosis fugax. Neither study described transient cortical blindness. Usually neuro-ophthalmologic complications of cardiac catheterisation relate to embolic phenomena or migraine. Cortical blindness is better recognised as a complication of cerebral and vertebral angiography, with an incidence of 0.3%–1.0%,8 but as high as 4% when hyperosmolar iodinated contrast agents are used.3 However, it can occur with newer low-osmolar and non-ionic radiographic contrast media, and this potential complication is indicated in the product information. Review of clinical information available from English language reports of transient cortical blindness after coronary angiography showed 17 cases.2-5,8-12 Thirteen of these involved men, and only four involved women, but this reflects the greater number of men who have coronary artery investigations. The average age of the patients was 58 years, and more than half (10 patients) had known systemic hypertension. Eleven (65%) had angiography of internal mammary artery grafts. Another five had additional aortography or coronary angioplasty. The volume of contrast dye used ranged from 80–400 mL. The time taken to recover normal vision varied from 15 minutes to three weeks, with an average of three days. Selective vertebral angiography carries the highest risk of neurological complication.13-15 As the internal mammary artery used for coronary grafting is adjacent to the origin of the vertebral artery, it is likely that a direct injection into the vertebral artery occurs. The cerebral reaction is not patient-specific, as later rechallenge with contrast medium has produced no recurrence.3 Minimising the amount of dye used is also advisable.3 PathophysiologyThe mechanism of cerebral injury remains speculative. It is thought that contrast agents disrupt the blood–brain barrier in the occipital lobes and exert a neuronal toxic effect.13 The posterior cerebral circulation is known to be more susceptible to such injury and this may relate to differences in sympathetic innervation.14 There may be a relationship to hypertensive encephalopathy, a clinical syndrome which can include visual disturbances. Imaging in hypertensive encephalopathy, including eclampsia, has shown bilateral abnormalities in the occipital lobes, involving the subcortical white matter and often extending to the cortical surface.16 Reversible oedema, localised mainly to the occipital lobes, is a prominent feature. Our patient was known to be taking drugs for chronic hypertension and had a documented acute blood pressure rise during the procedure. More than half the patients in previous reports had chronic hypertension, although the details of pressure changes during angiography have not usually been reported. Hypertensive encephalopathy is thought to result from sudden elevation of systemic blood pressure exceeding the auto-regulatory capacity of the cerebral vessels, producing regions of vasodilatation and vasoconstriction with a breakdown of the blood–brain barrier and focal transudation of fluid.16 These mechanisms seem possible in our patient, and they were supported by the results of imaging studies. There were bilateral occipital lobe changes when she had clinical cortical blindness (Box 1), representing oedema and passage of contrast across the blood–brain barrier. Cortical blindness is synonymous with bilateral homonymous hemianopia from involvement of the occipital cortex.1 When our patient was recovering and exhibiting right homonymous hemianopia, there were MRI changes in the left occipital gyrus, and differences in the calibre of the vessels on the two sides (Box 2). PrognosisIt is devastating for the patient, the family and the person carrying out the procedure when cortical blindness complicates coronary angiography. Cerebral embolism and haemorrhage have to be excluded by CT scan or MRI studies. Fortunately, the condition is usually transient. Lessons from practice Transient cortical blindness is a rare but alarming complication of coronary angiography. It has to be differentiated from an embolic problem. Computed tomography or magnetic resonance imaging is necessary. Oedema secondary to disturbance of autoregulation of the posterior cerebral vessels is a possible mechanism. Vision is usually recovered fully within a few days. 1: Computed tomography scan of the patient's brain three hours after completion of coronary angiography, when she had cortical blindness No additional contrast was given. There is marked bilateral contrast enhancement of the medial aspect of both occipital lobes in a symmetric distribution (arrows). 2: Magnetic resonance imaging (MRI) of the patient's head 48 hours after coronary angiography, when she had right homonymous hemianopia A: MRI (FLAIR image) shows increased signals in the medial aspect of the left (compared with the right) occipital gyrus separated by a fissure (arrow). Scattered foci of longstanding ischaemic damage on the rim of the lateral ventricles and frontal horns are consistent with the patient's age and risk factors. B: A magnetic resonance angiogram (MRA) at the same time shows that both posterior cerebral arteries are patent. The peripheral branches on the left side are larger (arrow).

Kiam K Lim MB BS · Dorothy J Radford MD FRACP

Evidence-based coronary care. Mark Connaughton. London: Churchill Livingstone, 2001 (xxii + 195 pp). ISBN 0443 06415 6. Clinicians working in the area of coronary care have the luxury of an enormous evidence base to guide their decision-making. Many of the so-called megatrials which have defined the modern era of evidence-based medicine were designed to answer important questions in acute coronary care. Making use of this evidence and applying it to patient care is a daily challenge for staff working in coronary care units. Mark Connaughton has done an excellent job in marshalling the evidence in a readable form and presenting it in a format which is easy to follow. On the left-hand page, concise recommendations are presented. On the right-hand page there is a summary of the published evidence, together with the key references. The reader obtains an immediate perspective on what is known and not known from the evidence. If the evidence is missing, the right-hand page is blank. This sensible and usable format could serve as a model for the presentation of clinical practice guidelines in general. The management of acute coronary syndromes is an area of rapid developments, so there are bound to be limits on the data presented. For instance, the statement “optimal strategies for managing unstable angina pectoris have not been determined and are an area of considerable current interest” has been rendered obsolete by recent trials and the development of detailed guidelines from the United States, Australian and European cardiac societies and heart associations. Unfortunately, the excellent format of the book is not followed in section 7. Here the author breaks his own rule by presenting tables, comments on electrocardiogram interpretation and “principles” on the right hand page which are not supported by published evidence. While there is much talk about downloading concise guidelines onto personal digital assistants (PDAs), this approach is limited by the fact that many junior medical and nursing staff do not have their own PDAs. Until the digital revolution has progressed to universal ownership of PDAs, Evidence-based coronary care is a neat solution to bringing evidence-based practice to the bedside of the patient with an acute coronary syndrome. Peter L ThompsonCardiologist Sir Charles Gairdner Hospital, Perth, WA

Peter L Thompson

Appropriate use of ambulatory blood pressure monitoring can be cost effective The rationale for the use of ambulatory blood pressure monitoring (ABPM) has been the subject of critical reviews and published guidelines.1-6 Perhaps the most important and challenging finding to emerge from ambulatory blood pressure research has been the detection of "white coat" hypertension (also known as isolated clinic hypertension) in about 20% of subjects with repeatedly elevated casual blood pressure readings taken in the doctor's clinic.7,8 The condition can only be detected by ABPM or self-monitoring, and there are no specific predisposing factors. For people with white coat hypertension and no evidence of cardiovascular disease or comorbidities such as diabetes or renal disease, most experts agree that the best policy is to monitor their clinic blood pressure regularly, with self-monitoring at home, and repeat ABPM at one- to two-yearly intervals. The importance of continued monitoring is borne out by the evidence now emerging that white coat hypertension may not be an entirely innocent phenomenon.5,6 The initial studies that examined the cost savings in the detection of white coat hypertension by ABPM7,8 did not consider the need for long-term surveillance and the conversion of patients with white coat hypertension to established hypertension; this might be as high as 75% over six years of follow-up.9 The development of hypertension on ABPM criteria could not be predicted by changes in clinic blood pressures. The cost-analysis study of ABPM in Australian general practice reported by Ewald and Perkarsky in this issue of the Journal (page 580)10 is important for a number of reasons. The study confirms the high prevalence of white coat hypertension previously reported in the Australian community,11 and reflects current general practice, because GPs decided on the basis of conventional clinic readings that drug treatment was indicated before ordering ABPM. This cost analysis is the first such study based on Australian data, including best estimates of current pharmacological management of hypertension in Australia. It has also factored in a 10% per year conversion rate from white coat hypertension to established hypertension. The sensitivity analysis showed that all monitoring strategies (ABPM at 1-, 2-, or 3-year intervals) were less expensive than no monitoring over a projected seven-year period. The study almost certainly underestimated the average costs of investigations of hypertension, including standard investigations, documentation of target-organ effects and specific investigations in selected subjects to exclude secondary hypertension. The potential costs of adverse drug reactions were not considered. However, both of these would amplify the difference towards greater cost saving with the use of ABPM. Another important attributable cost is that of the perception of unwellness that accompanies inappropriate labelling as "hypertensive", which can lead to loss of productivity, sick leave, anxiety and the development of symptoms. There are other groups of patients in whom ABPM might have cost-saving benefits. Staessen et al12 reported on a study in 419 patients randomised to be treated according to their daytime ambulatory blood pressure or their clinic blood pressure, with the latter group receiving usual care. The mean follow-up was six months, and the two groups had similar mean left ventricular mass at the end of the study. The ambulatory blood pressure group had a 19% decrease in antihypertensive drug use and an 11% fall in doctors' fees. Some treated hypertensive patients exhibit a marked difference between ambulatory blood pressure and clinic blood pressure, and assessment of the effectiveness of antihypertensive therapy using clinic blood pressure readings tends to overestimate responses to drug therapy by including the "placebo" component of the reduction in blood pressure, which is minimal with ABPM. The results of the Syst-Eur study of systolic hypertension show that conventional clinic blood pressure measurements lead to an overestimate of the prevalence of isolated systolic hypertension among elderly patients.13 This suggests the potential for excessive treatment and associated complications in a significant proportion of elderly patients. This white coat effect is reproducible.14 The recognition of white coat hypertension in pregnancy, which may occur in as much as 30% of pregnancies,15 has the potential to reduce anxiety, hospital admissions and drug use, with significant cost savings. Some notes of caution are warranted. A major one is that we still await the results of definitive outcome studies in controlled trials comparing management of hypertension based on clinic blood pressure versus ambulatory blood pressure. The technique of ABPM is specialised, and service providers must use validated monitors and quality control measures. Current provision of ABPM is not regulated in Australia and is not recognised through the Medical Benefits Scheme. Another cautionary note is that all available evidence suggests that hypertension in our community is more undertreated than overtreated. The use of self-monitoring is also increasing, although there are more concerns with self-recording devices. In a recent analysis,16 only five of 23 devices met acceptable criteria. A combination of the two has a lot to offer: ABPM may be better for the initial diagnosis of hypertension and for predicting prognosis, while self-monitoring may be of more value for the long-term follow-up of patients. ABPM is an important diagnostic tool in the management of hypertension. The study by Ewald and Perkarsky indicates that appropriate use can be of cost benefit to the Australian community.

Barry P McGrath MB BS MD FRACP

Objective: To compare the cost of ambulatory blood pressure monitoring (ABPM) with the putative savings made through treatment avoided by identification and non-treatment of those with "white coat" hypertension.Design: A cost analysis based on a model of four alternative strategies (no ABPM, yearly, two-yearly, or three-yearly monitoring) over a seven-year period applied to a case series from Australian general practice.Participants: 62 patients newly diagnosed by their GPs as having hypertension and requiring drug treatment.Main outcome measures: The proportion of patients shown to not need treatment. The discounted costs to the Pharmaceutical Benefits Scheme, Medical Benefits Scheme and patients.Results: 16 of 62 patients (26%; 95% CI, 15%–37%) were normotensive on ABPM and did not require treatment. All monitoring strategies are more expensive in the first year, but the initial costs are offset by year 3 and the monitoring strategies are cost saving thereafter. Sensitivity analysis shows that this result holds across a range of costs of pharmacotherapy and proportion of patients with white coat hypertension.Conclusion: The additional costs of 24-hour ABPM in the first year are offset by savings associated with patients with white coat hypertension who would otherwise have been treated.

Ben Ewald BMed, MMedSci(Epid) · Brita Pekarsky BEc(Hons), DipHEc

End-organ damage associated with hypertension is more closely related to ambulatory blood pressure (ABP) than clinic or casual blood pressure measurements. ABP measurements give better prediction of clinical outcome than clinic or casual blood pressure measurements. The technique of ABP monitoring (ABPM) is specialised; validated monitors and appropriate quality control measures should be used. Interpretation of ABP profile should include mean daytime, night-time (sleep) and 24-hour measurements, and consideration of diary information and time of drug treatment. Reports may also include ABP "loads" (percentage area under the blood pressure curve above set limits) for daytime and night-time periods. Normal blood pressure values for adults are < 135/85 mmHg for daytime, < 120/75 mmHg for night-time, and < 130/80 mmHg for 24 hours. ABPM is indicated to exclude "white coat" hypertension and has a role in assessing apparent drug-resistant hypertension, symptomatic hypotension or hypertension, in the elderly, in hypertension in pregnancy, and to assess adequacy of control in patients at high risk of cardiovascular disease. White coat hypertension requires continued surveillance; patients who display this phenomenon may, in time, develop established hypertension. Appropriate use of ABPM may result in cost savings. Randomised controlled trials comparing management based on clinic or casual versus ABP measurements are needed.

and on behalf of the National Blood Pressure Advisory Committee of the National Heart Foundation of Australia

To the Editor: The Lipid management guidelines — 2001 supplement1 is no doubt full of cardiovascular wisdom. Unfortunately, the authors appear oblivious to the fact that people are more than just cardiovascular systems. I found no mention of the risks of violent deaths associated with low cholesterol levels, which in some studies have been found to offset the decreased cardiovascular mortality benefits.2 In 1995, Engstrom et al neatly reviewed the relevant issues for those interested in populations of whole people. They cite studies which found low cholesterol levels to be associated with homicidal offenders with habitual violent tendencies when under the influence of alcohol, boys with aggressive conduct disorder, and criminals with antisocial personality, as well as with increased depressive symptoms in men aged 50–89 years. Further, an evaluation of six primary prevention trials found a significant increase in violent deaths in groups receiving interventions to reduce serum cholesterol levels.2 Engstrom et al also reviewed studies which found increased aggression in cynomolgus monkeys fed a low-fat diet. This appeared related to reduced serotonin activity, as serotonin is widely known to reduce aggression. In fairness, Engstrom and colleagues also cited studies which have not found an association between low cholesterol levels and aggression. If the increase in violent deaths associated with changing the dietary habits of whole populations turns out to be more than a red herring, the ethical and financial implications will be staggering. This evidence is not so conclusive as to have made me change my own relatively low-fat diet, but they do make me wonder if my irritation about the oversight in the Lipid management guidelines — 20011 might have something to do with my low fat intake!

Christopher H Cantor

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology. Clinically, it may present with systemic symptoms (eg, malaise, fever, anorexia), arthritis, photosensitivity, or organ injury (eg, glomerulonephritis). Myocarditis occurs in up to 10%1 of patients with SLE, but severe cardiac failure is very uncommon. We report our clinical experience of fulminant cardiac failure complicating SLE. Clinical recordA 24-year-old Vietnamese woman with intermittent haemoptysis was investigated as an outpatient. Culture of early-morning sputum was negative for tuberculosis, and a computed tomography (CT) scan of her chest showed right middle-lobe consolidation with no perihilar lymphadenopathy. Bronchoscopy showed active bleeding from the middle lobe of the right bronchus. Bronchial washings were negative for mycobacteria on acid-fast stain and culture, and no abnormal cells were found. Full-blood examination showed no abnormality; in particular, she did not have anaemia or lymphopenia. The erythrocyte sedimentation rate was mildly elevated at 29 mm/h (normal range, 0–15 mm/h) and rheumatoid factor was elevated at 30 kIU/L (normal range, 0–20 kIU/L). The presumptive diagnosis at this time was low-grade pneumonia. Subsequent investigations revealed a positive antinuclear antibody titre of > 1:1280 (normal, < 1:160), with a speckled pattern. As there was also a past history of Raynaud's phenomenon, small-joint hand arthritis and intermittent pleuritic chest pain, she was referred for rheumatological opinion. Two months after the onset of haemoptysis and before she could attend her rheumatology appointment, she presented to our emergency department feeling unwell, with a history of four days of fever, lethargy, dyspnoea, non-productive cough, nausea, vomiting and diarrhoea. Physical examination showed sinus tachycardia (130 beats/minute), a systolic blood pressure of 95 mmHg, cool peripheries and a dry tongue. Her jugular venous pulse was not visible. She was tachypnoeic (respiratory rate, 24 breaths/min), but auscultation of her chest showed no abnormality. She was given 1.5 L of normal saline intravenously over one hour for presumed dehydration. Subsequently, her condition deteriorated, with respiratory distress and pink, frothy sputum, and a chest x-ray revealed acute pulmonary oedema. Short runs of ventricular tachycardia were noted on her monitor. Electrocardiography showed sinus rhythm, right-axis deviation, Q waves in leads V1–V3, I and aVL, with high take-off in the ST segment in V1–V3. In subsequent ECGs, there was no evolution of the ST-segment change, indicating active myocardial ischaemia was unlikely. The level of cardiac troponin I was elevated at 9.6 µg/L (normal, < 0.04 µg/L). Her lymphocyte count was low at 0.81 × 109/L (normal, 1.0–4.0 × 109/L). The working diagnosis at this stage was acute heart failure secondary to a myocardial process such as acute myocarditis or valvular heart disease. Because of her respiratory distress, intubation was required and during this procedure her blood pressure fell further to 75/50 mmHg. Inotrope support was commenced with adrenaline at 10 µg/min. Urgent echocardiography confirmed severe global reduction in both left and right ventricular systolic function. Neither ventricle was dilated. There were no significant valvular abnormalities. A small pericardial effusion was present with no evidence of cardiac compression. Over the next two hours, despite an increasing inotrope infusion rate and insertion of an intra-aortic balloon pump, she had a low mean arterial pressure of 62 mmHg (generally, > 65–70 mmHg is required for major organ perfusion) and a low cardiac index of 2.1 (normal range, 2.5–3.6 L.min-1.m-2) (cardiac index = cardiac output per body surface area). She had no urine output. She was then placed on to extracorporeal membrane oxygenation (ECMO), and intravenous methylprednisolone (250 mg daily) was commenced. Over the next 24 hours, she developed acute renal failure — serum creatinine concentration peaked at 625 µmol/L (normal range, 40–120 µmol/L); ischaemic hepatitis — alanine transaminase level peaked at 3528 U/L) (normal range, 7–56 U/L); and coagulopathy — international normalised ratio (INR), 3.4 (normal range, 1.0–1.2); activated partial thromboplastin time (APPT), 44 s (normal range, 23–34 s); platelet count, 270 × 109/L (normal range, 150–450 × 109/L); fibrinogen level, 2.2 g/L (normal range, 1.5–4.0 g/L). Consequently, endomyocardial biopsy was not performed. After institution of ECMO, her condition stabilised and four days later she was able to be weaned off both ECMO and inotrope support. Renal and liver function returned to normal. Repeat echocardiography performed 10 days after admission showed a marked improvement in left ventricular systolic contraction, which was now only mildly reduced globally. Right ventricular function was normal. Other relevant test results are shown in the Box. Based on these results and the patient's clinical presentation, the rheumatologist diagnosed SLE. She was prescribed prednisolone (50 mg daily), azathioprine (50 mg daily), hydroxychloroquine (200 mg twice daily) and bone protective agents including alendronate sodium (70 mg once a week), calcium carbonate (600 mg at night) and ergocalciferol (1000 units daily). She was discharged 17 days after admission to a rehabilitation hospital and a week later she returned home. Six weeks after her emergency department presentation, she returned to work. DiscussionAcute myocarditis with severe cardiac failure and shock is a rare manifestation of SLE, with only a few cases reported.2-4 To our knowledge, this is the first in which ECMO was used and the patient survived. This case emphasises the importance of aggressive circulatory support to keep the patient alive and allow time for the potential recovery of the myocardium, either spontaneously or with corticosteroids. The reported use of ECMO support has predominantly been for postcardiotomy cardiogenic shock,5 and in cardiogenic shock related to acute myocardial infarction6 and acute myocarditis.7,8 Although the reported benefits of ECMO in these small studies vary considerably, for any patient to survive cardiogenic shock refractory to inotrope and intra-aortic balloon pump, with ECMO support, is a significant result. ECMO provides a bridge to recovery or to a decision about either heart transplantion or a ventricular-assist device. Partial or complete recovery of the myocardium in acute myocarditis with shock while receiving ECMO may be spontaneous or possibly facilitated by immunosuppressive therapy.7 The use of corticosteroid and other immunosuppressive therapy in acute myocarditis is controversial. A randomised trial,9 which studied patients with histological evidence of myocarditis and an ejection fraction less than 45%, did not find that prednisolone with either cyclosporin or azathioprine for 24 weeks improved ejection fraction or survival. However, a more recent trial10 found a significant improvement in ejection fraction and clinical status at two years in the group treated with three months of prednisolone and azathioprine. An immunohistological marker (upregulation of human leukocyte antigen [HLA]) was used on biopsy specimens to identify chronic myocarditis. Compared with histology alone, this marker selected a more homogeneous group of patients with inflammatory cardiomyopathy caused by active immune processes who may respond better to immunosuppression.10 There have been anecdotal reports of improvement in symptoms,2,3 and in left ventricular function,4 with the use of corticosteroids or immunoglobulins11 in severe cardiac dysfunction caused by SLE-related myocarditis. There is also some evidence of a better transplant-free survival in patients with fulminant, rather than non-fulminant, myocarditis if circulatory support was provided when they were critically ill.12 This suggests that more severe myocardial disease is associated with potentially greater reversibility of myocardial impairment. With the possibility of improvement, either spontaneously or with immunosuppressive therapy, it would be prudent to implement aggressive circulatory support with ECMO for patients with cardiogenic shock due to fulminant myocarditis who have failed to respond to inotrope support and intra-aortic balloon pump therapy. Results of immunological investigations Tests Results Reference range Antinuclear antibodies Positive (> 1:1280 titre), speckled pattern < 1:160 titre Anti-dsDNA 4 IU/mL 0–7 IU/mL Antibodies against extractable nuclear antigens Anti-La Positive Anti-Ro Positive Anti-RNP Negative Anti-Sm Negative Anti-Jo Negative Anti-Scl-70 Negative IgG anticardiolipin antibody 2.7 1.0–9.0 IgM anticardiolipin antibody 1.0 0.4–5.0 Lupus anticoagulant antibody Negative

Michael C H Leung MB BS(Hons) · Richard W Harper MB BS, FRACP · John Boxall MB BS, FRACP

To the Editor: A recent editorial in the Journal attempted to define a role for angiotensin II receptor (AIIR) antagonists in patients with type 2 diabetes.1 This was in the light of recent trial evidence that these agents reduce progression to renal failure in patients with type 2 diabetes and diabetic renal disease. Unfortunately, the guidelines provided were somewhat confusing and fragmented. I believe that a simpler treatment guide can be constructed, particularly when it is emphasised that the aim in diabetes is to use agents that prevent not only renal failure but also cardiovascular events. Substantial evidence already supports a role for the angiotensin-converting enzyme (ACE) inhibitor ramipril in treatment of diabetes. The HOPE study included 3577 people with diabetes and another risk factor for cardiovascular disease who were randomised to either placebo or ramipril (10 mg) for 4.5 years.2 This group had a mean baseline blood pressure of 142/80 mmHg and no clinical proteinuria. Ramipril lowered the risk of the combined primary outcome of myocardial infarction, stroke and cardiovascular death by 25% (P ≤ 0.001), and this effect was independent of blood-pressure lowering. Furthermore, ramipril reduced progression to overt nephropathy by 22%, with a reduction evident in patients with or without proteinuria.2 This protective effect of ramipril on renal function is consistent with previous evidence that ACE inhibitors slow progression of chronic renal failure in diabetes,3,4 and that ramipril slows progression of chronic renal failure in non-diabetic nephropathy.5 Whether other ACE inhibitors have the same effect as ramipril on cardiovascular events, and what doses obtain such an effect, remains speculative. Similarly, while there is now evidence that AIIR antagonists also have renal-protective effects, there is no definitive evidence that they protect against cardiovascular events. In view of this, and in the absence of comparative trials, ramipril (and not other ACE inhibitors or AIIR antagonists) is currently the first choice for treatment for diabetic patients with hypertension, with normotension and microalbuminuria, or with hypertension and micro- or macroalbuminuria. As most patients with diabetes and hypertension require multiple agents to achieve a target blood pressure less than 130/80 mmHg, additional therapy with a β-blocker, diuretic or calcium-channel blocker is often necessary. The significance of the newly available trial data is that AIIR antagonists provide an alternative to ramipril for reducing progression to chronic renal failure in patients with diabetic nephropathy who cannot tolerate ACE inhibitors because of the side effect of cough.

Roger E Peverill PhD, FRACP

In reply: Peverill raises the question of how to integrate the new data on renal protection by angiotensin II receptor (AIIR) antagonists with existing data on cardiovascular protection by angiotensin-converting enzyme (ACE) inhibitors in patients with type 2 diabetes. An AIIR antagonist would be favoured for renal protection for a diabetic patient with hypertension and evidence of early or overt nephropathy. With regard to patients with microalbuminuria, the HOPE and MICRO-HOPE studies showed that therapy with the ACE inhibitor ramipril (10 mg/day) was associated with a 24% relative risk reduction for the development of overt nephropathy over 4.5 years.1 In contrast, treatment of similar patients with the AIIR antagonist irbesartan (300 mg/day) for 2.6 years resulted in a 70% risk reduction for the development of overt nephropathy.2 Use of an AIIR antagonist in patients with overt nephropathy has also been shown to slow progression to end-stage renal failure.3,4 As the HOPE and MICRO-HOPE studies specifically excluded such patients, evidence supporting use of an ACE inhibitor in this context is lacking. An ACE inhibitor could be used if a diabetic patient has microalbuminuria and a history of coronary heart disease or additional risk factors for cardiovascular disease, especially if normotensive. However, almost all patients with microalbuminuria require antihypertensive therapy as well as therapy to protect target organs. The relative importance of blood-pressure-lowering versus non-lowering effects of antihypertensive therapy on reducing risk of cardiovascular disease remains uncertain.5 Furthermore, a recent meta-analysis of cardiovascular protection in 62 605 patients with hypertension (including the HOPE and United Kingdom Prospective Diabetes studies) did not find that ACE inhibitors affected cardiovascular prognosis beyond their antihypertensive effects.6 Finally, it is important to note that neither ACE inhibitors nor AIIR antagonists provide total protection from cardiovascular and renal events, and that further improvements are needed for both microvascular and macrovascular protection in patients with type 2 diabetes.

George Jerums · Mark E Cooper · Richard E Gilbert · Robert C Atkins