Cardiovascular diseases

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

Objectives: To determine the proportion of patients with established coronary heart disease (CHD) in two Australian studies (VIC-I in 1996–1998, and VIC-II in 1999–2000) who achieved their risk-factor targets as recommended by the National Heart Foundation of Australia, and to compare this proportion with those in studies from the United Kingdom (ASPIRE), Europe (EUROASPIRE I and II) and the United States (L-TAP).Design and setting: Prospective cohort study with VIC-I set in a single Melbourne university teaching hospital and VIC-II set in six university teaching hospitals in Melbourne, Victoria.Participants: 460 patients (112 in VIC-I, 348 in VIC-II) who completed follow-up in the control groups of two randomised controlled trials of a coaching intervention in patients with established CHD.Main outcome measures: The treatment gap (100%, minus the percentage of patients achieving the target level for a particular modifiable risk factor) at six months after hospitalisation.Results: The treatment gap declined from 96.4% (95% CI, 91%–99%) to 74.1% (95% CI, 69%–79%) for total cholesterol concentration (TC) < 4.0 mmol/L (P = 0.0001) and from 90.2% (95% CI, 83%–95%) to 54.0% (95% CI, 49%–59%) for TC < 4.5 mmol/L (P = 0.0001). This reduction in the treatment gap between VIC-I and VIC-II appears to be entirely explained by an increase in the number of patients prescribed lipid-lowering drugs. The treatment gaps in the UK and two European studies were substantially greater. The treatment gap for blood pressure (systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg) in VIC-II was 39.5%, again less than corresponding European data. There were 8.1% of patients who had unrecognised diabetes in VIC-II (fasting glucose level ≥ 7 mmol/L), making a total of 25.6% of VIC-II patients with diabetes, self-reported or unrecognised. The proportion of patients in VIC-II who were obese (body mass index ≥ 30 kg/m2) was similar to the overseas studies, while fewer patients in VIC-II smoked compared with those in the UK and European studies.Conclusions: A substantial treatment gap exists in Victorian patients with established CHD. The treatment gap compares well with international surveys and, at least in the lipid area, is diminishing.

on behalf of the COACH study group

Few events are harder to deal with than sudden death in young people. Each year in the United States, about one in 200 000 high school or college athletes will die suddenly, the vast majority without any prior symptoms,1 and these devastating events are often the first clinical manifestation of an underlying cardiovascular disorder. Indeed, about 90% of sudden deaths, defined as death occurring within one hour of the onset of symptoms, are found to be caused by cardiac structural pathology in autopsy-based series. The remaining 10% relate to other cardiac electrical disorders, such as long-QT syndrome and Wolf–Parkinson–White syndrome, or commotio cordis (the result of sudden sharp chest blows), as well as complications of asthma, substance misuse, and sudden infant death syndrome (SIDS).2 The single most common disorder causing sudden cardiac death in people aged less than 35 years, including competitive athletes, is the genetically inherited cardiac disorder hypertrophic cardiomyopathy (HCM).1 HCM is characterised by cardiac hypertrophy, usually of the left ventricle, in the absence of other loading conditions such as hypertension or hyperthyroidism. This disease occurs in approximately one in 500 people. It is clinically heterogeneous, with most affected individuals having few or no symptoms, while others develop serious complications, including heart failure, arrhythmias, and sudden death.3 In a series of 158 sudden deaths in young competitive athletes (median age, 17 years), 36% were found to have HCM and an additional 10% had evidence of increased cardiac mass suggestive of HCM.1 In Australia, 34 sudden deaths in people with HCM were reported to the HCM clinic at Sydney's Royal Prince Alfred Hospital over a five-year study period.4 A substantial proportion of patients with HCM die during or immediately after vigorous physical activity, but sudden death during rest or sleep is also common. The mechanism of death relates to ventricular arrhythmias in over 90% of known cases. Over the past decade, major advances have been made in understanding the genetic basis of many of the disorders which cause sudden death. DNA defects in disease-causing genes have been identified in HCM, as well as the long-QT syndrome, Marfan syndrome, dilated cardiomyopathy and arrhythmogenic right ventricular dysplasia. Over 200 mutations in at least 10 genes, all encoding proteins of the sarcomere (the basic contractile element of the heart), have been identified.5 Not only have such discoveries thrown light on the molecular pathogenesis of this disorder, but they have also enabled us to predict an apparently favourable or unfavourable clinical course.6,7 For example, many people in families with the Arg403Gln mutation in the beta-myosin heavy chain gene develop severe symptoms and even die by age 45 years. In contrast, individuals with the Val606Met mutation in the same gene usually appear to experience minimal symptoms and have a normal life expectancy.7 Clearly, understanding the molecular mechanisms by which gene defects lead to the clinical phenotype is important. To this end, the recent sequencing of the human genome8 offers the potential to identify more causative genes in HCM and other medical disorders. It also provides the possibility of understanding the mechanisms and signalling processes with which these genes regulate and modify gene expression (either by second disease-causing or modifying genes or environmental factors), leading to recognition of therapeutic targets important in the pathogenesis of sudden death (eg, ion-channel genes and genes regulating cardiac collagen formation). Pharmacological agents ranging from β-blockers to amiodarone, while frequently used, have not been shown to be effective in preventing sudden death in HCM. However, the implantable cardioverter-defibrillator has emerged as a proven therapy.9 Patients should be selected for implantable cardioverter-defibrillator implantation based on risk-stratification parameters. Proven predictors of sudden death which should identify patients who would most benefit from an implantable cardioverter-defibrillator are shown in the Box. Further, providing automatic external defibrillators in public places where crowds are present and where people may be at higher risk (eg, sporting venues) might be of significant benefit in reducing sudden cardiac death in this setting. In HCM, sudden death has been the most visible and devastating consequence of the disease since the original report by Teare over 40 years ago.10 Accurately identifying individuals at highest risk and initiating the most effective therapy to prevent this complication are clearly the ultimate goals. Understanding the genetic basis and molecular mechanisms underlying the cardiovascular disorders that cause sudden death, using this knowledge to identify potential new therapeutic targets, coupled with the use of established therapies such as implantable defibrillators, will go a long way to achieving these goals. Risk stratification and screening in sudden cardiac death Risk factors for sudden cardiac death Family history of premature sudden death Individuals with a family history of an inherited disorder associated with sudden death (eg, hypertrophic cardiomyopathy, long-QT syndrome) Previous cardiac arrest Previous episodes of documented ventricular tachycardia Recurrent syncope A known "malignant" gene mutation Specific risk factors for a disease (eg, left ventricular wall thickness greater than 30 mm in hypertrophic cardiomyopathy) Screening tests for family members at risk of sudden cardiac death History Physical examination 12-lead electrocardiogram Echocardiogram Other tests, such as Holter monitoring and exercise testing

Christopher Semsarian MB BS, PhD · Barry J Maron MD

The most important developments in cardiology and cardiac surgery in recent years have come from the implementation of ideas and techniques that have taken many years to bring to fruition. Prevention. Recognition that drugs may have multiple effects is a major advance. Statins reduce the incidence of recurrent vascular events because they decrease plasma lipid levels, and also because they reduce the likelihood of plaque rupture and subsequent thrombotic arterial occlusion. Angiotensin-converting enzyme (ACE) inhibitors control blood pressure, but also lower the risk of subsequent death, myocardial infarction and stroke,1 perhaps because they reduce adverse cardiac remodelling and modify vasomotor function. While we recognise the importance of risk factors such as obesity and lack of fitness, patient compliance, smoking and low rates of treatment of hypertension and dyslipidaemias remain major problems. Diagnosis. Echocardiography continues to improve technically, and, for most patients, is the definitive investigation of cardiac morphology and function. Small portable machines that can be used as an extension of physical examination may revolutionise practice. Magnetic resonance imaging rivals echocardiography for examining the heart and great vessels, and can evaluate myocardial perfusion and viability. However, its inaccessibility and expense mean it will not displace echocardiography for most patients. Electron beam computed tomography (CT) can show coronary artery calcification, but its value in screening for disease is not yet clear. Contrast studies with multislice spiral CT show details of coronary artery morphology and may replace angiography for some purposes. Despite much research into the genetic basis of cardiovascular diseases, knowledge and technology are not yet sufficiently developed for this to be clinically useful. Intervention. The use of serum markers of myocardial damage (eg, troponin) has redefined the spectrum of acute coronary syndromes2 and improved identification of high-risk patients, for whom early angiography and revascularisation by angioplasty (with platelet glycoprotein IIb/IIIa inhibitors) or surgery is warranted. The best way to limit damage and reduce mortality in patients with myocardial infarction is to restore flow in the infarct-related artery as soon as possible. When it can be done promptly enough, angioplasty is safer and more effective than lysis.3 Issues of prehospital delay, diagnosis by paramedics before admission and the availability of interventional services need to be addressed. Thrombolysis, perhaps initiated in ambulances on the way to hospital, still offers the best outcome for most patients. It is difficult to compare angioplasty with surgery for treating chronic angina because of continuous modifications and improvements in both fields. While angioplasty is now usually combined with stenting, surgeons now prefer arterial conduits to saphenous vein grafts because of their superior long-term patency, and have developed techniques such as grafting the beating heart without cardiopulmonary bypass, limited-access surgery and even robotic surgery to reduce morbidity. In patients with multivessel disease who might be helped by either technique, angioplasty with stent deployment is as successful and safe as surgery,4 but more often requires further interventions because of restenosis. The use of stents which elute an immunosuppressive drug (eg, sirolimus) may reduce this risk, but surgery will still be necessary for chronically occluded vessels, for most lesions of the left main trunk, and probably for multivessel disease in patients with diabetes. Chronic heart failure is becoming more prevalent. There is excellent evidence for the value of ACE inhibitors, ß-blockers and spironolactone. A small number of patients will still undergo transplantation, but ventricular-assist devices (implanted pumps) may offer definitive treatment rather than simply a bridge to transplantation. Treatment of arrhythmias has changed. The perceived usefulness of antiarrhythmic drugs (apart from ß-blockers) for suppressing ventricular tachyarrhythmias has declined. Class 1 agents such as quinidine are now rarely used as they may be pro-arrhythmic. Radiofrequency ablation can cure most recurrent supraventricular arrhythmias, but the best approach to managing atrial fibrillation remains unclear. Complex implanted devices can pace for bradycardia, suppress ventricular tachycardia and terminate ventricular fibrillation,5 but cost limits their widespread use. The best hope for reducing mortality from out-of-hospital cardiac arrests may be to provide automatic defibrillators in public places. Conclusion. The benefits of developments in imaging, percutaneous coronary intervention and surgical innovation are limited by poor compliance (particularly in modifying risk factors). Ultimately, society must decide how much we can afford to spend on such expensive developments as magnetic resonance imaging or implantable defibrillators.

J H Nicholas Bett MB BS, FRACP · Malcolm J West · R Bruce Garlick

Medicine and the media Trial of a trial by media In a democratic society, the Press has the right to investigate any issue it chooses, but this right should come with a responsibility for accuracy and freedom from bias Helge H Rasmussen, Peter S Hansen, Yutaka Koyama, Barbara-Ann Adelstein, Anthony J O'Connell and Gregory I C Nelson MJA 2001; 175: 625-628 Rationale for the trial - The trial - Consent - The risks of our trial - Lessons from the obstacles to the trial - Conclusions - References - Authors' details - - More articles on Journalology and publishing Articles in the Sydney broadsheet, the Sydney Morning Herald (SMH), earlier this year reported that some doctors were concerned about the safety, ethics and lack of informed consent of a clinical trial proposed for the management of acute myocardial infarction (AMI). The New South Wales Minister for Health, Mr Craig Knowles, was made aware of the SMH journalists' investigation, and, by the time the articles appeared in the broadsheet, he was reported to have stopped implementation of the trial.1,2 A prominent radio commentator highlighted the serious nature of the perceived problems by asking rhetorically "Do we have to have someone who actually dies before it becomes a scandal?".3The fate of this clinical trial has implications for the conduct of clinical research. Here, we outline the rationale for the trial and the risks for participants in it, and discuss ethical issues related to consent to participate in clinical trials. We also question the ethics of the process that led to the trial being stopped. Rationale for the trial Treatment of AMI with fibrinolytic agents is firmly established. However, its efficacy in achieving the treatment goal of opening the occluded coronary artery is limited and re-occlusion occurs frequently.4,5 Furthermore, many patients have contraindications to fibrinolysis, usually because they are deemed to be at high risk of bleeding. They may also be considered unsuitable for fibrinolysis, mostly because an electrocardiogram does not show the changes associated with proven benefit. AMI remains a common and frequently fatal condition. Recent prospective registry data on 30 402 patients with AMI indicate that the cumulative mortality rate remains high at about 14% while in hospital and about 22% by 90 days after presentation.6Percutaneous coronary intervention (PCI) has been introduced to improve outcomes of AMI. When PCI is used in the treatment of AMI, an angioplasty balloon is used to unblock the occluded culprit coronary artery. A stent is then often deployed to maintain the patency of the artery. Small, randomised trials indicate that PCI is superior to fibrinolyis when performed in heart centres by experienced teams.7,8 However, most patients, even those residing in urban areas, live outside the catchment area of major hospitals. An extension of the benefits of PCI to these patients could be achieved by establishing cardiac interventional units in their local hospitals, but such units would have a low case load. Studies have shown that institutions and operators with a low case load do not achieve better patient outcomes with PCI than with fibrinolysis.9-11 We chose to examine an alternative approach involving early transport of patients to a specialised "Regional Heart Attack Centre". The trial Patients presenting to the Ambulance Service with suspected AMI within the geographic limits of the Northern Sydney Area Health Service, but outside the normal catchment area of Royal North Shore Hospital (RNSH), were to be allocated at random to treatment at their local district hospital or at RNSH. Our trial was to compare two strategies: one based on PCI, backed by facilities at a large centre, and the other based on treatment with fibrinolytics at local hospitals with fewer facilities. Our comparison between the two strategies was to be based on the number of deaths and the number of recurrent non-fatal myocardial infarctions and non-fatal strokes in the two groups of patients during the admission for AMI and six months later. Our trial was designed to determine if there were benefits of a PCI-based strategy at a large centre despite the additional transport time. The potential benefits of such a strategy might be considerable. Careful analysis of registry data on AMI indicated that the hospital mortality rate for patients treated at small centres without facilities for PCI is almost twice as high as that at large centres with facilities for PCI.8,12 Had our randomised, controlled trial replicated these results, it would have indicated that many lives could be saved with centralised care of all patients with AMI in large cities in a few, highly specialised Regional Heart Attack Centres. Because of the urbanised distribution of our population, many patients in Australia would stand to benefit. However, such centralised treatment would require a major change from current practice and have important consequences for resource allocation. (See the Box for a flow diagram of the proposed trial.) In 1997, the RNSH institutional ethics committee requested that we perform a pilot study to document that we could reproduce the published results of PCI on a seven-days-a-week, 24-hours-a-day basis before a randomised study could be considered. The pilot study (Stenting Strategy as an Alternative to Lytic/Medical Therapy in Acute Myocardial Infarction — SALAMI) started on 1 July 1997 and was completed in November 1998. It was confined to patients eligible for fibrinolysis within the RNSH catchment area. No inhospital deaths occurred in 102 patients.13 PCI became our standard treatment at RNSH for all patients with AMI. Subsequent outcomes for patients in a wide age range with virtually no exclusions have remained excellent,14 and much better than expected for the alternative strategy based on fibrinolysis/medical therapy. Despite these good outcomes, the SMH reported that there were concerns about the trial related to risks to participants and lack of fully informed consent. Consent The medical executive officer of a private hospital publicly articulated his concern about consent and was quoted in the SMH as saying: I think the lack of consent is a very fundamental issue of weakness in the trial. I think it is an abrogation of fundamental human rights. I can't imagine how they got it past their ethics committee. What they are saying is that the benefits justify them overlooking that basic human right. I don't know anybody who knew anything about ethics would agree with that.2 A subsequent editorial in the SMH emphasised that "patients should be informed totally about proposed treatments".15 Truog et al hold a different opinion, and maintain that blind insistence on consent can preclude evidence-based improvement in care of acute critical illness and can be viewed as harmful.16 We concur with their judgement. Truly informed consent is difficult to give in any trial, and particularly difficult for patients with an acute critical illness. There is little evidence that informed consent protects patients from exploitation in research. This is highlighted by patients' poor understanding of consent forms and the process of randomisation, even when these decisions apply to elective treatment.16 The understanding of consent has been examined for participants in the PARAGON-B and OASIS-2 studies (which investigated the use of platelet antagonists in unstable angina and non-Q-wave myocardial infarction). Understanding of the benefits of participation was good at 85%. However, only 35% of participants understood the risks and very few (10%) understood that there was an alternative to participation. Not surprisingly, pain was an adverse predictor for comprehension.17 In our proposed trial, pain would be an almost universal feature at the time informed-consent had to be given, and the need to administer reperfusion therapy as early as possible would not allow much time for the informed-consent process. Inevitably, comprehension would have been even worse than in the PARAGON-B and OASIS-2 studies.17 The difficulty with giving informed consent in our trial was illustrated by the articles in the SMH. The paper provided a reasonably accurate account of the trial in the first articles it published,1,2 but we doubt whether the editorialist (unsigned), writing three days later, understood the trial's purpose. Indeed, he/she questioned "why the trial is necessary at all".15 When customary informed consent cannot be obtained, one can choose from three options: Not to conduct the research For life-threatening conditions for which treatment is unsatisfactory not conducting research is unacceptable, as it may deny patients their right to optimal care.18 To change treatment without trial evidence Changing treatment without trial evidence might be applauded as "clinical innovation" and does not require ethics approval. There is virtually no protection of patients from even the most adventurous "clinical innovation".16 For the issues that were to be addressed by our trial, a change in treatment strategy would be based on comparisons between rather than within studies. Regardless of how compelling such comparisons may seem, the superiority of a treatment cannot be established without randomised, controlled trials.19 To have an ethics committee assume the responsibility of giving consent on behalf of patients. The best way to protect patients from exploitation in trials involving patients with acute critical illness is by getting an ethics committee to carefully scrutinise the protocol and agree to assume the responsibility of giving consent in the acute phase of the illness.16 Patients should then be fully informed about their participation and rights as soon as reasonably feasible. This approach is in complete accordance with Australian guidelines on the ethical conduct of research on humans,20 and was adopted for our trial. It was an important feature of our protocol that patients allocated at random to treatment at RNSH would be asked if they agreed to be taken there before the ambulance started its journey. A patient who declined would be taken to the local district hospital and receive standard care. We reject the assertion that they were to be "press-ganged".15 However, there is no pretence that it would have been feasible to obtain patients' truly informed consent. The SMH expressed the view that absence of informed consent in our trial might set "a dangerous precedent".2 This also has no foundation in fact. Proper research for the "Herald investigation" would have revealed that the first and best-known large-scale trial to document efficacy of fibrinolysis was conducted without informed consent. An institutional review board had found that informed consent could not be obtained in patients with AMI.21 Our trial would not have set any precedent. The risks of our trial An institutional ethics committee can not consider a trial unless the risk of the intervention under investigation is reasonable compared with that of existing therapy.22 According to the SMH our trial was a high-risk venture.15 One article stated "it is generally acknowledged by doctors that one in every four heart attack victims will die within the first hour if emergency treatment is not given".2 A cardiologist offered an estimate of what the delays might be: "I would want to know that I wasn't going to be delayed by two hours when I could have had thrombolytic agents in 10 minutes."2 Another cardiologist expressed similar concerns.3 We agree risks would be unacceptable if there were additional delays of two hours and a 25% mortality rate per hour. However, the implication that such risks would be imposed by our trial is not consistent with the facts. Patients with AMI tend not to seek help early, and typically arrive in hospital about two hours after the onset of symptoms.6,23 The pre-hospital cardiac arrests that do occur usually happen before arrival of an ambulance.23,24 New South Wales ambulances are equipped with defibrillators and ambulance officers can provide care for patients with cardiac arrest which is as good as or better than that provided by medically trained personnel.25 A reversible cardiac arrest can be safely dealt with during transport, a conclusion supported by experience with interhospital transfers of patients with AMI,26 including those at particularly high risk.27 It is very unlikely that any trial patient who had a reversible cardiac arrest during transport to RNSH would die. Let us also consider the alleged treatment delays of two hours versus 10 minutes. Transport of patients to district hospitals takes time and the median time to administration of fibrinolytics after patients arrive is up to 45 minutes.6,28 The only transport time difference that matters is that between transport within the catchment area of a district hospital and transport to RNSH. Data from direct transport to the RNSH trauma centre, by-passing district hospitals, show a mean difference of 20 minutes for the most remote area.29 This is less than the difference in in-hospital delays for patients with AMI who arrive within or outside normal working hours and are treated with PCI -- we cannot detect any adverse effects of these delays.14 In fact, outcomes for patients treated during either period are much better than expected for a treatment strategy based on fibrinolysis. Available evidence suggests that the overall risk for patients transported to RNSH is likely to be lower than the risk for patients taken to district hospitals and treated in accordance with established strategies. Lessons from the obstacles to the trial The results of the SALAMI pilot study (which was completed in 1998)13 satisfied the RNSH ethics committee's request for documentation of patient outcome. However, we were then asked to provide a response to complaints lodged with the Australian Federation of University Women Inc Northern Beaches Group, the NSW Health Care Complaints Commissioner, the Australian Medical Association, the NSW Director General of Health, local political leaders, community groups, the National Health and Medical Research Council (NHMRC), and the Cardiac Society of Australia and New Zealand. (Documentation relating to these complaints and our responses is available on request.) The Health Care Complaints Commissioner recommended that the trial be referred to the NSW State Ethics Committee. This committee referred the trial back to the RNSH ethics committee, with long delays occurring in the process. However, approval was eventually given. Complex practical arrangements for implementation of the trial were near completion when the SMH announced that the NSW Minister for Health had decided to refer the trial to "an area ethics committee yet to be formed, which would comply with National Health and Medical Research Council guidelines".2 We emphasise that the RNSH Human Research Ethics Committee had been constituted, and operated, strictly in accordance with NHMRC guidelines. It was also reported that the new ethics committee would meet "in the next few weeks".2 In reality, constitution of an ethics committee is a complex process, and more than four months passed before the new committee had its first meeting. Additional long delays have already occurred in processing our proposal completely, independently of the careful, lengthy deliberations of the original committee. The main concerns expressed by opponents of the trial related to the ethics of the trial, particularly its lack of fully informed consent. However, there are situations in which it is impossible to reconcile the doctrines of informed consent with the practical necessities of research, and depriving patients of the potential benefits of research can, in some circumstances, be considered unethical.22 The guidance for treatment and health policy, which the trial had the potential to provide, might have saved many lives. However, the trial was delayed because of the many complaints lodged about it, and it was ultimately stopped as a direct consequence of the SMH's investigation. The published investigation1,2 misrepresented the trial's rationale, risks and important ethical issues. The NSW Minister for Health acted on the information made available to him. He may have had little choice under the circumstances. However, the end result was that due process suffered. Conclusions In a democratic society, the Press has the right to investigate any issue it chooses, and individuals have the right to lodge complaints with any authority they see fit. However, these rights should come with a responsibility for accuracy and freedom from bias. Society now has a justified expectation of medical practice based on evidence, and processes are in place to ensure the ethical conduct of the necessary research to produce this evidence. These processes may be in need of protection from sensationalism based on suppositions rather than evidence and expertise. The establishment of ethics committees with guaranteed protection from interference, similar to the protection for courts, should be considered. References Ryle G. Radical heart attack fix under fire. The Sydney Morning Herald 2001; 29 March: 1. Ryle G. A trial of the heart. The Sydney Morning Herald 2001; 29 March: 11. Sydney radio station 2UE. Malcolm Elliott 10.10 am, 1 April 2001. Presenter discusses plans to divert emergency heart attack patients to Royal North Shore Hospital. Interview with Dr Ross Walker, Sydney Adventist Hospital. (Transcript available on request.) The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both, on coronary artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615-1622 Meijer A, Verheught FWA, Werter CJPJ, et al. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischaemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Circulation 1993; 87: 1524-1530. Rogers WJ, Canto JG, Barron HV, et al. For the Investigators in the National Registry of Myocardial Infarction. Treatment and outcome of myocardial infarction in hospitals with and without invasive capability. J Am Coll Cardiol 2000; 35: 371-379. Gersh BJ. Primary angioplasty reduced rate of death, reinfarction or disabling stroke. Evidence-based Cardiovasc Med 1997; 1: 105-106. Every NR, Lehmann KG. The effectiveness of primary PTCA: does patient risk matter? J Am Coll Cardiol 2001; 37: 1836-1838. Every NR, Parsons LS, Hlatky M, et al. A comparison of thrombolytic therapy with primary coronary angioplasty for acute myocardial infarction. Myocardial Infarction Triage and Intervention Investigators. N Engl J Med 1996; 335: 1253-1260. Magid DJ, Calonge BN, Rumsfeld JS, et al. Relation between hospital primary angioplasty volume and mortality for patients with acute MI treated with primary angioplasty vs thrombolytic therapy. JAMA 2000; 284: 3131-3138. The GUSTO-IIB angioplasty substudy investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activators for acute myocardial infarction. N Engl J Med 1997; 336: 1621-1628. Zahn R, Schiele R, Schneider S, et al. Primary angioplasty versus intravenous thrombolysis in acute myocardial infarction: can we define subgroups of patients benefiting most from primary angioplasty? J Am Coll Cardiol 2001; 37: 1827-1835. Hansen PS, Rasmussen HH, Vinen J, Nelson GIC. A primary stenting strategy as an alternative to fibrinolytic therapy in acute myocardial infarction. Med J Aust 1999; 170: 537-540. Koyama Y, Hansen PS, Rasmussen HH, Nelson GIC. August 2001. What are the delays in primary infarct angioplasty when performed after hours and do they influence outcomes? Presented at the 49th Annual Scientific Meeting of the Cardiac Society of Australia and New Zealand. Aust N Z J Med. Abstract. In press. Medicine on trial. Editorial. The Sydney Morning Herald 2001; 2 April: 12. Truog RD, Robinson W, Randolph A, Morris A. Is informed consent always necessary for randomized, controlled trials? N Engl J Med 1999; 340: 804-807. Kucia AM, Horowitz JD. Is informed consent to clinical trials an "upside selective" process in acute coronary syndromes? Am Heart J 2000; 140: 94-97. Grim PS, Singer PA, Gramelspacher GP, et al. Informed consent in emergency research. Prehospital thrombolytic therapy for acute myocardial infarction. JAMA 1989; 262: 252-255. White HD. Thrombolytic therapy in the elderly [editorial]. Lancet 2000; 356: 2028-2030. National Health and Medical Research Council. National Statement on Ethical Conduct in Research Involving Humans. Canberra: NHMRC, 1999: 28-29. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Lancet 1986: 1: 397-401. Foëx BA. The problem of informed consent in emergency medicine research. Emerg Med J 2001; 18: 198-204. Holmberg M, Holmberg S, Herlitz J, Gardlov B, for the Swedish Cardiac Arrest Society. Survival after cardiac arrest outside hospital in Sweden. Resuscitation 1998; 36: 29-36. Norris RM, on behalf of the United Kingdom Heart Attack Study Collaborative Group. Fatality outside hospital from acute coronary events in three British health districts 1994-5. BMJ 1998; 316: 1065-1070. Holmberg M, Holmberg S, Herlitz J, for the Swedish Cardiac Arrest Society. Factors modifying the effect of bystander cardiopulmonary resuscitation on survival in out-of-hospital cardiac arrest patients in Sweden. Eur Heart J 2001; 22: 511-519. Widimsky P, Groch L, Zelizko M, et al. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE Study. Eur Heart J 2000; 21: 823-831. Straumann E, Yoon S, Naegli B, et al. Hospital transfer for primary coronary angioplasty in high risk patients with acute myocardial infarction. Heart 1999; 82: 415-419. Thiemann DR, Coresh J, Schulman SP, et al. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 2000; 101: 2239-2246. Harris R. Forget the golden hour. Proceedings of the First International Conference of the Australasian-Canadian Trauma Society, Darling Harbour, Sydney; March 2001. Abstract. Injury. In press. (Received 25 Jun, accepted 10 Oct, 2001) Authors' details Department of Cardiology, Royal North Shore Hospital, St Leonards, NSW. Helge H Rasmussen, FRACP, DMSc, Professor of Cardiology, Department of Medicine, University of Sydney; Peter S Hansen, FRACP, PhD, Senior Lecturer, Department of Medicine, University of Sydney; Yutaka Koyama, MD, PhD, Interventional Fellow; Gregory I C Nelson, MB BS, FRACP, Director, Cardiac Catheterisation Laboratory, and Coronary Care Unit. Ambulance Service of New South Wales, Sydney, NSW. Barbara-Ann Adelstein, MB BCh, MBA, Medical Director. Anthony J O'Connell, FANZCA, FFICANZCA, Chairman, Medical Advisory Committee, Ambulance Service of NSW. Reprints will not be available from the authors. Correspondence: Professor H H Rasmussen, Department of Cardiology, Royal North Shore Hospital, St Leonards, NSW 2065. helgerATmed.usyd.edu.au Make a comment Flow diagram of the proposed trial of two models of care for patients with acute myocardial infraction. Back to text

Helge H Rasmussen · Peter S Hansen · Yutaka Koyama · Anthony J O'Connell

Medicine and the media Media milking of sacred cows: a heart-stopping tale Were there alternative frames that could have attracted journalistic interest in this trial? MJA 2001; 175: 629-630 In 1897, William Osler advised doctors not to "toy with the Delilah of the press".1 Despite researchers being generally delighted with journalists' translations of their work into news2 (few would disagree with Mae West that it's better to be looked over than overlooked), Osler's counsel sadly retains widespread support in the health professions. For too many, journalists spell trouble. Some who have been bruised by what they consider trite, sensationalised or misleading news reports of their research assume that journalists are mere ciphers for doctors and scientists, providing a sort of popular scientific abstracting service which is falling down in its duty. While the news media may be an arm of the health service in some countries, they play an entirely different role in open societies like Australia. Here, facts frequently serve as pretexts to publish richly subtextual moral tales intended to resonate with readers, retain their loyalty and, in expanding readership, attract greater advertising revenue. Journalists' routines are governed by ambitions to get on the front page and break "exclusive" news that will ripple for days through their rival's news media. When this ambition dovetails with public health and the wider public interest, most are happy to applaud the media as a highly influential force for good. But, when popular news frames are invoked to negatively frame potential advances in patient care or public health, the media can be a powerfully conservative force that can damn progress. 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. Health and medicine are rich with news value.3 Doctors are cast by the news media in many roles:4 for example, as medical miracle workers;5 as sages interpreting issues of contemporary morality; as intrepid, no-stone-unturned disease detectives;6 or as entrepreneurs. Rasmussen and colleagues, who describe their experience with the media in this issue of the Journal,7 perceived their role as just trying to save the lives of patients with acute myocardial infarction (AMI). They aimed to compare the outcomes of transporting patients with AMI to a large centre with facilities for angioplasty and stenting with the conventional wisdom of rushing them to the nearest hospital for standard treatment. These researchers were following the long tradition of those who have sought to improve survival rates through a randomised controlled trial. But reporter Gerald Ryle and his editors at the Sydney Morning Herald judged other news frames to be more compelling. They chose to see the story as one of doctors who, "believing their own omnipotence", "press-ganged" vulnerable people into some dangerous and radical "experiment".8,9 Ryle's reports,8,10 the Herald's editorial,9 and their sequelae voiced by radio commentators, framed the trial as an example of arrogant doctors dicing with patients' lives. The main ingredients of the "story" were the notions that two inviolable conventions were being trampled underfoot. Blind Freddy — or the Herald's editorial writer — knows that transporting a person having an infarct to the nearest hospital without delay, and obtaining patient consent to treatment, are sacrosanct. The transportation issue taps into the same ordinary person's outrage when a local hospital is closed, and politicians explain that patients are better served by travelling the extra distance to a larger hospital. In criticisms of this aspect of the trial, the important question of whether patients might actually benefit by travelling the extra distance was lost. Both the righteous indignation of the accusations that patient consent to involvement in the trial would not be obtained, and the restrained dissection by Rasmussen et al of the folly of that indignation, will cause many heads to shake in disbelief. 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. To describe this as being "press-ganged" was sure to produce popular outrage. Were there alternative frames that could have just as easily attracted journalistic interest in this trial? Opposition had often been voiced in local newspapers, because of implications for local hospitals of the trial's possible success. If it showed important patient benefit, local coronary care facilities may have been downgraded, with all the downstream implications. "Doctors seek to stop life saving heart trial", with an investigation of the motives and interests of local opposition to the trial, might have been another headline that defined the same events with rather different outcomes. Alan Otten, with the Wall Street Journal for 44 years, notes that "Well done investigative reporting produces public outrage . . . Ten-thousand-watt klieg lights turned on a situation focuses the minds of policy makers very fast."11 Ryle's front-page arc lights precipitated ministerial intervention, stopping a trial that may have led to many lives being saved. The sacred cow of the shortest possible ambulance ride remains intact, as presumably does the despair of those hoping to use research to find ways of improving survival rates after AMI. The history of medicine is full of tumultuous episodes where accepted procedures were challenged by innovators and where the orthodoxy stood to lose from the change.12 This episode adds to that litany, but hopefully will not jaundice what is so often a mutually productive relationship between medicine and the media. Simon Chapman Professor, Department of Public Health and Community Medicine University of Sydney, Sydney, NSW Competing interests: None declared. Osler W. Internal medicine as a vocation. [Address given at the New York Academy of medicine, October 19, 1897.] Reprinted in McGovern JP, Roland CG, editors. The collected essays of Sir William Osler, vol. II. Birmingham, AL: Classics of Medicine Library; 1985: 151. Phillips DP, Kanter EJ, Bednarczyk B, Tastad PL. Importance of the lay press in the transmission of medical knowledge to the scientific community. N Engl J Med 1991; 325: 1179-1183. Lupton D. Medical and health stories on the Sydney Morning Herald's front page. Aust N Z J Public Health 1995; 19: 501-508. Lupton D, McLean J. Representing doctors: discourses and images in the Australian press. Soc Sci Med 1998; 46: 947-958. Lupton D, Chapman S. Death of a heart surgeon: some thoughts about press accounts of the murder of Victor Chang. BMJ 1991; 303: 1583-1586. Brown J, Chapman S, Lupton D. Infinitesimal risk as public health crisis: media coverage of a doctor to patient HIV contact tracing investigation. Soc Sci Med 1996; 43: 1685-1695. Rasmussen HH, Hansen PS, Koyama Y, et al. Trial of a trial by media. Med J Aust 2001; 175: 625-628. Ryle G. Radical heart attack fix under fire. Sydney Morning Herald 2001; 29 March: 1. Medicine on trial [editorial]. Sydney Morning Herald 2001; 2 April: 12. Ryle G. A trial of the heart. Sydney Morning Herald 2001; 29 March: 11. Otten AL. The influence of the mass media on health policy. Health Affairs 1992; Winter: 111-118. Porter R. The greatest benefit to mankind. A medical history of humanity from antiquity to the present. London: Fontana,1999 . Make a comment

Simon Chapman

Medicine and the media Clinical research in the emergency setting: the role of ethics committees It is important that discussions and decision-making processes be free, open and transparent MJA 2001; 175: 630-631 Probably because of its mixed history of triumph and abuse, medical research has always been regarded with a combination of awe and suspicion. Not surprisingly, research into innovative technologies and dangerous illnesses arouses particular anxieties, and sometimes public controversy. The complexities associated with clinical research in the emergency setting are illustrated by the story recounted in this issue of the Journal of the trial proposed by investigators at Sydney's Royal North Shore Hospital (RNSH) to compare two models of care for patients with acute myocardial infarction (AMI).1 While fibrinolysis has been standard treatment for AMI since the mid-1980s, evidence has suggested that coronary artery angioplasty with stenting produces better outcomes. However, the latter treatment requires advanced technology and skills, limiting its availability. Accordingly, it was proposed to conduct a randomised trial to compare outcomes for patients with AMI of transport to the nearest regional hospital for "conventional" treatment versus transport to RNSH for possible angioplasty. . . . the scientific questions are well founded and the answers are likely to carry significant implications for medical practice around the world. Two major issues were recognised from the outset: Patients assigned to RNSH would often experience increased transport times to hospital; and It would be difficult to obtain patients' fully informed consent. The first issue is important because delays in initiating treatment after AMI increase the risk of death. The second issue of difficulty obtaining informed consent is encountered in research involving interventions for acute, life-threatening illness, because of shortness of time and the inevitable stress associated with the life-threatening circumstances. Both these issues were taken up by the RNSH ethics committee that meticulously examined the study. After examination of preliminary data, the committee accepted the arguments of the investigators that the benefits of stenting would exceed any increased risk associated with transport delays. It was also decided that it was acceptable to delay provision of detailed information about the trial until the patients arrived at RNSH, even though, in reality, this would often exclude alternatives. Despite complaints provoked by concern within the medical community, approval was eventually granted, but before the trial could begin the Sydney Morning Herald published an article questioning this decision.2 A storm of publicity followed and, months later, the trial has still not commenced. There are several points raised by this case on which there is widespread agreement. In the emergency setting, as elsewhere, rigorous testing is important to identify the most effective treatments and to exclude ineffective, risky or unnecessarily expensive ones. However, the gravity and urgency of the circumstances will often limit the extent to which patients can make carefully considered judgements about whether to participate. Often compromises need to be found. It is the sometimes unenviable job of the responsible ethics committee to attempt to find such a compromise, after considering all the issues and balancing possible risks and benefits. In this case, the scientific questions are well founded and the answers are likely to carry significant implications for medical practice around the world. However, whatever decision is ultimately reached it is unlikely to find acceptance by all protagonists. The complexity of the issues emphasises the importance of the ethics committee process. As with the courts, public confidence in the outcome of ethics committee deliberations depends on a belief that it is fair, free from interference and takes into account all relevant issues. The RNSH ethics committee appears to have acted with propriety and professionalism, but, like other ethics committees, its deliberations are not open to public scrutiny. In addition, it is possible that it did not consider issues affecting other hospitals within the region — for example, the interests of private providers of angioplasty and their patients who could be disadvantaged by the study. The absence of the need to justify decisions in contentious cases, and of a defined appeals process for most committees, creates an appearance of arbitrariness and peremptoriness. The role of the media, which the investigators found so disturbing here, also raises important issues. Medical research is a matter of public interest, and ethics review is not a mere technical function, but a means by which the community ensures that research proposals are adequately evaluated and supervised. Press coverage may be of variable quality, and may itself represent undeclared vested interests. However, as cumbersome and inconvenient as the process may be, if a study has sufficient merit and the review process has been sufficiently robust it is unlikely that public debate and critical reflection will ultimately prevent it from proceeding. This imbroglio provides several important lessons. There are no short cuts to the solution of difficult ethical problems and complete consensus may never be possible. What is most important is that discussions and decision-making processes be free, open and transparent. For these reasons, the tendency for ethics committees to keep their deliberations secret, in the mistaken belief that this is necessary to protect intellectual property, should be reassessed. Promising new models for ensuring public accountability and sharing of experience of committee processes should be examined, such as open access to meetings, chat rooms and the concept of the health ethics archive.3,4 In addition, care must be taken to ensure that current efforts to streamline ethics review processes in the interests of cost and efficiency do not erode the democratic, decentralised nature of the system. In the case of the RNSH trial of treatment for AMI, the investigators should be encouraged to continue dialogue with their interlocutors until the best possible compromise can be reached. Paul A Komesaroff Director, Monash Centre for the Study of Ethics in Medicine and Society Melbourne, VIC Competing interests: None declared. Rasmussen HH, Hansen PS, Koyama Y, et al. Trial of a trial by media. Med J Aust 2001; 175: 625-628. Ryle G. A trial of the heart. Sydney Morning Herald 2001; 29 March: 11. The Institutional Review Board — discussion and news forum. <http://www.irbforum.org> (accessed November 2001). Health Ethics Archive. <http://www.ethics-archive.org> (accessed November 2001). Make a comment

Paul A Komesaroff

Editorial Are the new Lipid Management Guidelines good for Australia's health? Recommendations, possibly resulting in the long-term treatment of one million Australians, require a serious cost-benefit analysis MJA 2001; 175: 452-453 The new Australian Lipid Management Guidelines 2001, published as a supplement with this issue of the Journal, provide an excellent overview of the current evidence on the cardiovascular disease (CVD) benefits of cholesterol lowering. They also signal the acceptance by Australian experts that treatment decisions should be driven primarily by a patient's estimated "absolute CVD risk" — the probability of developing CVD over a specified time period — rather than primarily by his or her blood lipid level. The Guidelines comprehensively summarise the extensive evidence showing the benefits of cholesterol-lowering interventions in people with low-density lipoprotein (LDL) levels above about 2.5-3.0 mmol/L (equivalent to a total cholesterol level above about 4.5-5.0 mmol/L). But they don't tell us that over 90% of Australians aged 45-75 years have a total cholesterol level above 4.5 mmol/L (Dr Danny Liew, Department of Epidemiology and Preventive Medicine, Monash University, VIC, unpublished analysis). The Guidelines correctly emphasise the need to base treatment decisions primarily on absolute CVD risk rather than on lipid levels, as the benefits of cholesterol lowering are determined far more by individual absolute risk than by pre-treatment level of LDL cholesterol. But the advice provided on how to identify patients at high absolute risk, particularly those without previous symptomatic disease, is rather loose, as discussed below. Moreover, the potential size of the target group for drug-based primary prevention is not mentioned. ...it is estimated that this year statins will account for almost a fifth of the total Australian Pharmaceutical Benefits Scheme budget. Lipid-lowering drugs are appropriately recommended for secondary prevention when the total cholesterol level is above 4 mmol/L, given the high absolute risk and large potential benefit of treatment. This patient group includes about 5% of Australians aged 30-79 years (Professor Andrew Tonkin, National Heart Foundation Australia, personal communication). Aboriginal people and Torres Strait Islanders are appropriately identified as high-risk groups, as are people with diabetes (types 1 and 2), although the recommended treatment threshold for Indigenous people and people with diabetes is unclear. If the cholesterol threshold for treatment is also 4 mmol/L in these groups, I estimate this will add at least another 5% of the middle-aged and older Australian population to the numbers eligible for treatment. The authors of the Guidelines endorse the CVD risk charts used in New Zealand for estimating absolute CVD risk.1 This brings Australian lipid management recommendations more in line with those of the international community. Similar charts or risk calculators, all based on data from the Framingham Heart Study, are now included in most major national and international CVD management guidelines.2-6 The Guidelines state that people with an estimated five-year absolute CVD risk of 10%-15% or above (identified using risk charts) are the "at-risk" group who should be targeted for treatment. Alternatively, for doctors who don't use risk charts, the at-risk group includes everyone over 45 years of age with at least one of seven listed risk factors, some of which are ill-defined in the Guidelines (ie, "hypertension" and "overweight"), yet are very prevalent using some common definitions. For people less than 45 years of age, having two listed risk factors also places them in the at-risk group. This "count the risk factors" definition of at-risk is an unnecessarily crude approach and will identify some people with only a 5% five-year CVD risk and exclude others with a five-year risk above 15%. It is also difficult to find a clear statement in the Guidelines about when to initiate drug treatment in this "at-risk" group, and no mention is made of the potential size of the group. I estimate it will include at least another 20% of Australians aged 45-75 years if the cut-off for drug treatment is an LDL cholesterol level of 4 mmol/L or a total cholesterol level of 6 mmol/L (Professor Michael Hobbs, Department of Public Health, University of Western Australia, personal communication). The authors of the Australian guidelines are to be congratulated for their high quality review of the evidence of effectiveness of both population- and individual-level interventions, and for explicitly linking the level of evidence with their recommendations. However, they are remiss in not considering the implications of implementing the recommendations. For example, it is estimated that this year statins will account for almost a fifth of the total Australian Pharmaceutical Benefits Scheme budget.7 While this may or may not be good value for money, it is increasingly accepted that clinical leaders, as well as taking responsibility for individual patients, must also consider the wider resource implications of their recommendations. The practical implications and potential alternative uses of the substantial dollar and people resources required to implement these recommendations should have been considered. For example, it may (or may not) be better value to fund more coronary angioplasties, or to develop more comprehensive rehabilitation programs for patients who have had a myocardial infarction, than to give statins to hundreds of thousands of Australians with a modestly raised risk of CVD. It would also be illuminating to estimate the implications of these recommendations for health professionals, particularly general practitioners and dietitians. It may be that the implementation costs of the new Lipid Management Guidelines 2001 are justified by the magnitude of the benefits. But recommendations that could result in the long-term treatment of perhaps one million Australians, require a substantial amount of general practitioner and dietitian time and consume a significant proportion of the national pharmaceutical budget will require a serious cost-benefit analysis if they are to be endorsed by healthcare funders. Healthcare costs will be cut by insiders with a scalpel or by outsiders with a meat axe.7 In their current form, these Guidelines unfortunately present an exposed neck to a large axe. Rodney T Jackson Professor; and Head, Division of Community Health and Effective Practice Institute, Faculty of Medical and Health Sciences, University of Auckland, NZ Jackson R. Updated New Zealand cardiovascular disease risk-benefit prediction guide. BMJ 2000; 320: 709-710. Dyslipidaemia Advisory Group. 1996 National Heart Foundation clinical guidelines for the assessment and management of dyslipidaemia. N Z Med J 1996; 109: 224-232. Wood D, Durrington P, Poulter N, et al. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80 (Suppl 2):S1-S29. Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis 1998; 140: 199-270. Guidelines Subcommittee. 1999 World Health Organization - International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999; 17: 151-183. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA 2001; 285: 2486-2497. Health Insurance Commission. Annual Report 1999-2000. <www.hic.gov.au/statistics/dyn_pbs/forms/pbs_tab1.shtml> Eddy D. What do we do about costs? JAMA 1990; 264: 1161-1170. Make a comment

Rodney T Jackson

Notable Cases Caffeine-induced cardiac arrhythmia: an unrecognised danger of healthfood products We describe a 25-year-old woman with pre-existing mitral valve prolapse who developed intractable ventricular fibrillation after consuming a "natural energy" guarana health drink containing a high concentration of caffeine. This case highlights the need for adequate labelling and regulation of such products. Marianne E Cannon, Clive T Cooke and James S McCarthy MJA 2001; 174: 520-521 Clinical record - Discussion - References - Authors' details - - More articles on Toxicology While caffeine is widely used in most Western societies, caffeine toxicity is rare, and certainly rarely diagnosed. Case reports of death from caffeine toxicity number approximately 20 in the medical literature.1-3 We report a case of sudden death in a young woman which was associated with ingestion of caffeine present in guarana, a widely available health supplement marketed as a "natural" source of energy, and targeted to young people in advertising. Clinical record A 25-year-old woman had been working at a bar where she was seen to collapse. Police at the scene started cardiopulmonary resuscitation shortly afterwards. An ambulance arrived several minutes later and she was defibrillated according to ambulance protocol, with a total of 12 defibrillation attempts. She arrived at the emergency department in ventricular fibrillation and was resuscitated according to advanced cardiac life support guidelines for a further 20 minutes. At no stage did she regain a spontaneous cardiac output. Further history (which became available later) indicated that the patient had been diagnosed with mitral valve prolapse. She had been referred to a cardiologist because of palpitations. He had raised the issue of caffeine intake, and she had agreed to limit this to a cup of tea daily. Her previously recorded resting electrocardiogram was normal, with no evidence of QT prolongation. On the day of her death she had been given a 55 mL squirt bottle of "Race 2005 Energy Blast with Guarana and Ginseng", which she had nearly emptied. Other staff working at the bar had also been given bottles of Race 2005. She had not consumed other caffeine-containing substances. At autopsy, the patient was found to have sclerosis and myxoid change of the mitral valve leaflets. A toxicological screen for all common prescribed and non-prescribed drugs (including opiates, cannabis, amphetamines, and cocaine metabolites) was performed. Assay methods included gas chromatography and mass specrometry (GC-MS) and immunoassay. Caffeine was detected by GC-MS; the toxicology screen was negative for other substances. High pressure liquid chromatography revealed a caffeine concentration of 19 mg/L (non-preserved) in aortic blood. The caffeine concentration in the bottle of Race 2005 Energy Blast was assayed at the Chemistry Centre of Western Australia and yielded a level of 10 g/L, which is more than 60 times the concentration of caffeine in cola beverages (see Box).4 A similar bottle was later shown to have a caffeine concentration of 19 g/L. Discussion The wide availability and toxicology of "natural" tonics and remedies and the regulation of such substances has been the subject of vigorous debate in both the lay press and the medical literature.6-10Guarana is produced from the seeds of the guarana plant (Paullina cupana), a creeping Amazonian shrub. The seeds are black "like an eye" and contain 3.6%-5.8% caffeine.11 The substance is named after the Guarani Amazonian tribe, who originally used the seeds to brew a drink.11 In Brazil, guarana is commonly used as an astringent, a flavouring, and as a stimulant, and it is increasingly being used in similar products internationally. Such products are widely available at pharmacies and natural food outlets, and are marketed as natural sources of energy. Caffeine is a natural alkaloid methylxanthine. Ninety-nine per cent is absorbed after oral ingestion, the blood concentration peaks 1-1.5 hours after ingestion, and its half-life in adults is 3-6 hours. Caffeine is metabolised by the P450 hepatic enzyme system.12 The pharmacodynamic profile of caffeine is similar to that of theophylline, another methylxanthine, in that it inhibits the adenosine receptor and acts as a phosphodiesterase inhibitor.12 At high serum levels, enzyme saturation occurs, and elimination follows zero-order kinetics, with constant elimination regardless of serum level.12 Caffeine increases intracellular calcium concentrations, causes noradrenaline release and sensitises dopamine receptors. The pharmacological effects of caffeine include central nervous system (CNS) and cardiac stimulation, as well as coronary vasodilatation. It relaxes smooth muscle, stimulates skeletal muscle, has a weak diuretic action, and its metabolic effects include hypoglycaemia. While toxicity generally occurs at serum levels over 25 mg/L, the correlation between concentration and clinical effects is poor.4 The measured concentration of 19 mg/L in our patient may reflect postmortem changes in drug level, or an enhanced sensitivity to caffeine toxicity in this patient. The measured concentration is the equivalent of what would result from drinking approximately 15-20 cups of coffee.4 The toxic effects of caffeine include vomiting and abdominal pain followed by CNS symptoms, including agitation, altered conscious state, rigidity and seizures.4 Cardiovascular effects include supraventricular and ventricular tachyarrhythmias, and significant metabolic disturbances may occur, including hypokalaemia and hyperglycaemia. Suggested management for caffeine toxicity, in addition to general supportive measures, includes multidose charcoal therapy, and extracorporeal elimination by charcoal haemoperfusion.13 One proposed mechanism for the seizures and cardiac arrhythmias is the blockade of adenosine receptors.12 Thus, there is a theoretical rationale for the use of adenosine in this setting, particularly if seizures are refractory to benzodiazepine agents.14 Likewise, as there is adrenergic stimulation, parenteral -blocker therapy (propranolol or esmolol) should be considered for treating ventricular arrhythmias.15 Most deaths associated with caffeine intoxication have occurred after overdose with diet pills and stimulants, and most have occurred in young patients without known underlying heart disease or variant of normal, such as mitral valve prolapse. At least two case reports document sudden death in patients who "walked" into an emergency department.14 After the death of our patient, the Western Australian Coroner recommended that Race 2005 Energy Blast be removed from the local market, and the product was recalled nationally by letter to distributors in August 1999. However, many other products containing guarana (eg, "energy" tablets containing 35 mg of caffeine each, as well as a variety of energy drinks) remain available Australia-wide. With the growing use of guarana-based products containing high levels of caffeine, there is an obvious potential for lethal overdose. Our patient had a relatively common cardiac abnormality, present in 2.4% of the population.16 While mitral valve prolapse has been associated with sudden death, the risk of this is low.17 Malignant arrhythmias may occur in the absence of cardiac stimulants, but the association of arrhythmia with drugs that increase cardiac irritability is well known. The role of caffeine in this woman's death is supported by her history of palpitations associated with caffeine ingestion, a history that had prompted her cardiologist to advise her to limit her caffeine intake. In this patient's case the Coroner found that the high level of caffeine was associated with the development of an intractable arrhythmia. This case highlights the need for more careful regulation of "natural" products, including warnings for patients with underlying health problems, and clear labelling to document the presence of any constituents with potentially toxic effects. It also shows the need for medical practitioners to be familiar with the more widely used "natural"-remedy substances, and their toxicological profile. Acknowledgements: We thank Dr Julian Stella and Dr Peter Sprivulis for their assistance in the preparation of this manuscript. Disclosure: We did not receive any financial or other support for this work, and have no financial or professional relationships that may pose a conflict of interest. References Garriott JC, Simmons LM, Poklis A, Mackell MA. Five cases of fatal overdose from caffeine-containing "look-alike" drugs. J Anal Toxicol 1985; 9: 141-143. Mrvos RM, Reilly PE, Dean BS, Krenzelok EP. Massive caffeine ingestion resulting in death. Vet Hum Toxicol 1989; 31: 571-572. Walsh I, Wasserman GS, Mestad P, Lanman RC. Near-fatal caffeine intoxication treated with peritoneal dialysis. Pediatr Emerg Care 1987; 3: 244-249. Lewin NA. Caffeine. In: Goldfrank LR, editor. Goldfrank's toxicologic emergencies. 6th ed. Stamford: Appleton & Lange, 1998: 555-562. Abbott PJ. Caffeine: a toxicological overview. Med J Aust 1986; 145: 518-521. Angell M, Kassirer JP. Alternative medicine — the risks of untested and unregulated remedies. N Engl J Med 1998; 339: 839-841. De Smet PA. Should herbal medicine-like products be licensed as medicines? BMJ 1995; 310: 1023-1024. Ernst E. Harmless herbs? A review of the recent literature. Am J Med 1998; 104: 170-178. Shaw D. Risks or remedies? Safety aspects of herbal remedies in the UK. J R Soc Med 1998; 91: 294-296. Kessler DA. Cancer and herbs. N Engl J Med 2000; 342: 1742-1743. Duke JA. CRC Handbook of medicinal herbs. Boca Raton: CRC Press, 1985. Serafin WE. Drugs used in the treatment of asthma. In: Hardman JG, Limbird LE, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996. Nagesh RV, Murphy KA. Caffeine poisoning treated by hemoperfusion. Am J Kidney Dis 1988; 4: 316-318. Shum S, Seale C, Hathaway D, et al. Acute caffeine ingestion fatalities: management issues. Vet Hum Toxicol 1997; 39: 228-230. Pentel P. Toxicity of over-the-counter stimulants. JAMA 1984; 252: 1898-1903. Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 1999; 341: 1-7. Duren DR, Becker AE, Dunning AJ. Long-term follow-up of idiopathic mitral valve prolapse in 300 patients: a prospective study. J Am Coll Cardiol 1988; 11: 42-47. (Received 5 Oct 2000, accepted 13 Mar 2001) Authors' details Department of Emergency Medicine, Fremantle Hospital, Fremantle, WA. Marianne E Cannon, MB BS, FACEM, Emergency Medicine Staff Specialist. PathCentre, QEII Medical Centre, Nedlands, WA. Clive T Cooke, BMedSci, FRCPA, Forensic Pathologist. University of Western Australia, Department of Medicine, Fremantle Hospital, Fremantle, WA. James S McCarthy, MB BS, FRACP, Senior Lecturer. Reprints will not be available from the authors. Correspondence: Dr M E Cannon, Department of Emergency Medicine, Fremantle Hospital, Fremantle, WA 6959. mariannecannonAThotmail.com Make a comment Caffeine content of various food, drinks and medicines Substance Defined dose* Concentration Tea 40mg per cup (approx.) 0.16g/L Coffee 100mg per cup (approx.) 0.4-1.6g/L Chocolate (30g) 4mg Cola 0.15g/L Diet pills 75-200mg Race 2005 (30mL "dose") 300-570mg 10-19g/L *After Lewin4 and Abbott.5 Back to text

Marianne E Cannon · Clive T Cooke · James S McCarthy

Editorial Heart failure in older people: the epidemic we had to have Optimal treatment of the increasing number of patients with chronic heart failure will be a major challenge MJA 2001; 174: 432-433 The perception of most Australians of heart disease is the 1960s stereotype: middle-aged men suffering cardiac emergencies such as myocardial infarction, with dramatic symptoms, frantic therapeutic effort and frequently fatal outcome. However, this scenario has become the exception rather than the rule — the age-adjusted incidence of myocardial infarction and of cardiac death is falling in Australia, as in most Western countries,1 although this fall is less clear-cut in lower socioeconomic groups.2 It is possible... that the prescribing habits of GPs are directed towards agents which are likely to produce rapid relief of symptoms Despite these gains, recent evaluations indicate that the prevalence of heart disease in most communities is rising steadily, and that this is reflected in costs of hospitalisation if not in mortality data.1 This rise suggests that the strategies directed at reducing risk of ischaemic heart disease (such as cessation of smoking and lowering of serum cholesterol level) should be regarded as means of postponing disease onset rather than as "vaccines" against eventual ischaemia. Therapies such as thrombolytic agents3 and coronary angioplasty4 for patients with acute myocardial infarction, and β-adrenoceptor antagonists5 and angiotensin-converting enzyme (ACE) inhibitors6 for those with symptomatic heart failure, have led to increased survival rates, and thus more individuals with chronic heart disease. In addition, in older people, increasing rates of atrial fibrillation and aortic stenosis also contribute to cardiac disability. The Cardiac Awareness Survey and Evaluation (CASE) Study examined the current contributions of general practitioners to the diagnosis and management of chronic heart failure (CHF) in patients over the age of 60 years. The results, published in this issue of the Journal,7 shed considerable light on the magnitude of this emerging problem in Australia. One of the most complex questions in cardiology is the diagnosis of CHF. In the vast majority of controlled clinical trials to date, the diagnosis of CHF has been predicated on objective evidence of left ventricular systolic dysfunction, documented by echocardiography or radionuclide ventriculography. Most intervention studies have only included patients with severe systolic dysfunction, in order to maximise the frequency of end-points. Yet, this is just the tip of the CHF iceberg in the general population. For patients with predominantly diastolic, or mild degrees of systolic, left ventricular (LV) dysfunction, estimation of LV ejection fraction alone provides little diagnostic information, and the diagnosis of CHF becomes somewhat arbitrary. This was so in some patients in the CASE study: it is clear that GPs do not use echocardiography widely to assess patients with possible CHF. This blurring around the edges of the diagnosis (especially in patients with mild dysfunction) is regrettable, but there is no easy solution. Conversely, however, it is impossible to exclude from the CASE study design a number of patients with LV dysfunction but minimal symptoms, a group which may benefit from appropriate pharmacotherapy. Overall, one recommendation from the CASE study, which resulted in new diagnosis of CHF in 2% of the study population, is that widespread access to echocardiography by GPs for people older than 60 years is likely to be cost effective. The major stimulus to the diagnosis of CHF is the institution of appropriate therapy. It is here that the CASE study is most revealing. There have been dramatic advances in the management of CHF in the past 15 years, resulting in considerable improvement in outcomes for this patient population,8 although there is clearly scope for further reductions in both morbidity and mortality.9 ACE inhibitors (preferably in the largest tolerated dose),6 spironolactone10 and β-adrenoceptor antagonists5 all reduce mortality and morbidity in patients with LV systolic dysfunction. There is also evidence for the use of angiotensin-receptor antagonists or hydralazine/nitrates in patients intolerant of ACE inhibitors. Digoxin, in patients in sinus rhythm, has no major effect on mortality but slightly reduces hospitalisation risk.11 Conversely, some agents, notably calcium antagonists12 and the COX-1 (and possibly the COX-2)13 inhibitors, should be used with caution in patients with CHF, and the role of diuretic therapy is probably limited to the prevention of peripheral and/or pulmonary oedema. It is therefore an important finding of the CASE study that, even in the hands of an "interested" cohort of GPs, ACE inhibitors were used in little more than half of the patients, and usually with low-dose regimens. In contrast, use of diuretics and digoxin was surprisingly high. This makes it clear that in Australia, as in other countries,14 CHF is largely under-treated, and the price we pay is increased risk of deterioration, hospitalisation and death. It is possible, although not specifically examined by the CASE study, that the prescribing habits of GPs are directed towards agents which are likely to produce rapid relief of symptoms rather than agents with prognostic benefits. The epidemic of CHF in older people has its counterpart in an explosion of recent relevant clinical trial information. The HOPE study results suggest that all patients at high risk of ischaemia should be considered for treatment with ACE inhibitors, irrespective of the presence or absence of CHF.15 The data on the beneficial effect of spironolactone are quite recent, as are some of the β-adrenoceptor antagonist data. It is also clear that community-based outreach services for CHF patients may improve outcomes.16 Identification of and optimal therapy for these patients constitutes a major challenge for the new millennium. John D Horowitz Professor of Cardiology University of Adelaide, and Director Cardiology Unit North Western Adelaide Health Service, Adelaide, SA Simon Stewart Ralph Reader Postdoctoral Fellow Department of Public Health University of Glasgow, Glasgow, UK Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 1999; 353: 1547-1557. Morrison C, Woodward M, Leslie W, Tunstall-Pedoe H. Effect of socioeconomic group on the incidence of, management of, and survival after myocardial infarction and coronary death: analysis of community coronary event register. BMJ 1997; 314: 541-546. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet 1994; 343: 311-322. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. N Engl J Med 1997; 336: 1621-1628. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001-2007. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999; 100: 2312-2318. Krum H, Tonkin AM, Currie R, et al. Chronic heart failure in Australian general practice. The Cardiac Awareness Survey and Evaluation (CASE) Study. Med J Aust 2001; 174: 439-444. MacIntyre K, Capewell S, Stewart S, et al. Evidence of improving prognosis in heart failure: trends in case-fatality in 66,547 patients hospitalised between 1986 and 1995. Circulation 2000; 102: 1126-1131. Stewart S, MacIntyre K, MacLeod MM, et al. Trends in hospitalisation for heart failure in Scotland, 1990-1996. An epidemic that has reached its peak? Eur Heart J 2001; 22: 209-217. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709-717. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997; 336: 525-533. O'Connor CM, Carson PE, Miller AB, et al. Effect of amlodipine on mode of death among patients with advanced heart failure in the PRAISE trial. Prospective Randomized Amlodipine Survival Evaluation. Am J Cardiol 1998; 82: 881-887. Dzau VJ, Packer M, Lilly LS, et al. Prostaglandins in severe congestive heart failure. Relation to activation of the renin-angiotensin system and hyponatremia. N Engl J Med 1984; 310: 347-352. Edep ME, Shah NB, Tateo IM, Massie BM. Differences between primary care physicians and cardiologists in management of congestive heart failure: relation to practice guidelines. J Am Coll Cardiol 1997; 30: 518-526. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145-153. Stewart S, Marley JE, Horowitz JD. Effects of a multidisciplinary, home-based intervention on unplanned readmissions and survival among patients with chronic congestive heart failure: a randomised controlled study. Lancet 1999; 354: 1077-1083. Make a comment

John D Horowitz · Simon Stewart

Henry Krum, Andrew M Tonkin, Robert Currie, Robert Djundjek and Colin I Johnston MJA 2001; 174: 439-444 For editorial comment, see Horowitz & Stewart; see also Krum Abstract - Methods - Results - Discussion - Acknowledgements - Reference - Authors' details - - More articles on Cardiology and cardiac surgery Abstract Objectives: To investigate the frequency and general practitioner awareness of patients with chronic heart failure (CHF), and to evaluate a cardiac algorithm and document cardiac investigations performed in establishing this diagnosis. Design and setting: Between March and August 1998, consecutive patients aged 60 years and older presenting to their GP were assessed. In patients previously diagnosed with CHF, aetiology and diagnostic assessments were documented. In patients with suspected CHF (by a standardised algorithm, based on World Health Organization guidelines), further investigations and GP diagnosis were recorded. Patients: 80 consecutive patients were assessed by each of 341 GPs throughout Australia, reflecting the Australian metropolitan/rural population mix of 1996. This provided a total of 22 060 evaluable patients. Main outcome measures: Estimated numbers of patients with CHF in general practice (previously and newly diagnosed); major aetiological factors; use of ancillary diagnostic tests; drugs prescribed. Results: CHF was diagnosed in 2905 of 22 060 patients (13.2%) (2485 previously diagnosed and 420 newly diagnosed). Major aetiological factors were ischaemic heart disease and hypertension. Echocardiography had been performed in 64% of previously diagnosed patients, but was performed in only 22% of possible CHF patients. Angiotensin-converting enzyme (ACE) inhibitors were prescribed in 58.1% of patients with CHF. Patients with evidence of left ventricular dysfunction were more likely to have received ACE inhibitors. Conclusions: CHF appears to be very common in the elderly, based on GP diagnosis of the condition. Of 100 patients aged 60 years and over presenting to their GP, two new cases of CHF will be detected using a simple clinical algorithm in conjunction with appropriate diagnostic tests. ACE inhibitors appear to be underutilised. Chronic heart failure (CHF) is a debilitating condition with high morbidity and mortality, and is a major public health burden. Its prevalence is increasing,1 despite a reduction in age-standardised mortality associated with cardiovascular diseases such as myocardial infarction and stroke.2 Factors implicated in this increased prevalence include the ageing of the population, decreased mortality rates following myocardial infarction, and more frequent diagnosis of CHF after investigations such as echocardiography.3The epidemiology of CHF in Australia has been assumed to be similar to that in the United States,4-6 the United Kingdom7-10 and Europe.11,12 However, substantive data have been lacking, and the approach taken to diagnosis of patients with suspected CHF in general practice in Australia is also unknown. Similarly, although international studies have suggested marked underutilisation of angiotensin-converting enzyme (ACE) inhibitors and β-blockers,4-11,13-17 no evaluation of use of drug therapies for CHF in Australia has been reported. Accordingly, the aims of the Cardiac Awareness Survey and Evaluation (CASE) Study were: to investigate the frequency, awareness, and aetiology of heart failure in general practice in Australia; to document cardiac investigations used by general practitioners in establishing the diagnosis of CHF; and to determine prescribing patterns in the treatment of CHF by Australian GPs. As the prevalence of heart failure increases steeply with age, the study focused on people aged 60 years and older. Methods Recruitment into the CASE study GPs were recruited solely on the basis of interest in participating in the study. Interest was first ascertained by the local pharmaceutical representative of the study sponsor (see Acknowledgements). The CASE steering committee then sent interested GPs a formal letter of invitation to participate in the study. GPs agreeing to participate attended a local education and information session. These sessions were spread across all Australian States and Territories with a mix of metropolitan, rural and remote regions in an effort to recruit a sample of GPs (and thus patients) representative of their distribution. Each GP was asked to assess 80 consecutive patients aged 60 years or older for the possibility of heart failure. GPs were recruited from March 1998, data were collected prospectively and the study was completed in August 1998. Assessment for CHF New patients: Patients not previously diagnosed as having CHF were assessed for that possibility using modified World Health Organization criteria (Box 1).18 Alternative conditions that may have contributed to these symptoms and signs were recorded. In patients suspected of having CHF based on the above criteria, further investigations (chest x-ray [CXR], electrocardiogram [ECG], and echocardiogram) were suggested (but not mandated). GPs were also asked to note any investigations that had been performed in the previous 12 months. For patients who had an echocardiogram, the GP was asked to indicate whether there was evidence of systolic or diastolic ventricular dysfunction (or both) from the echocardiogram report. At the conclusion of this process, the GPs assessed whether they thought the patient had CHF. Previously diagnosed patients: For patients who had previously been diagnosed as having CHF by their GP, records were retrospectively analysed for clinical and diagnostic criteria that contributed to that diagnosis. These included use of ECG, CXR and echocardiography, hospital admission for heart failure, and specialist referral for CHF. Pharmacotherapy For patients with previously diagnosed CHF, GPs were asked to document current drug therapy specifically prescribed for this condition (name of drug, daily dose, and frequency of administration). For patients with newly diagnosed CHF, GPs were asked whether they instituted pharmacotherapy immediately and what that pharmacotherapy comprised. A dosage equivalence table of commonly prescribed ACE inhibitors was compiled, and prescribing was divided into low, medium and high doses. To determine prescribing according to decade of life, prescribing was assessed in patients aged 60-69 years (n = 569), 70-79 years (n = 1360), and 80 years and older (n = 976). GP prescribing in patients with echocardiographic evidence of systolic or diastolic left ventricular dysfunction was specifically determined. Initial pharmacotherapy prescribed for patients diagnosed with CHF as part of the CASE study was evaluated. Because of the cross-sectional nature of the assessment in CASE, most of these patients did not have the opportunity to be up-titrated to target doses of drugs. For this reason, newly diagnosed patients were not included in the analysis of dose of ACE inhibitor prescribed. Results Of 523 GPs who originally expressed interest in participating, 341 completed the study. Their geographical distribution (78% metropolitan, 22% rural or remote) was similar to that observed for all Australian GPs (77% metropolitan, 23% rural or remote). In all, 23 845 patients were entered into the study. Of these, 1785 were excluded from analysis because of patient refusal or missing data, leaving 22 060 who made up the baseline population. Baseline demographics The distribution of the CASE patient population by area (capital city, 58.7%; metropolitan, 10.7%; rural, 21.4%; remote, 1.2%; 8% unclassified) was similar to the 1996 Australian population aged 60 years or older.19 However, there were fewer rural patients among the CASE cohort than in the census population. The total CASE study population comprised 45% men and 55% women; 8612 (39%) were aged 60-69 years (48% men), 9371 (42.5%) were aged 70-79 years (45% men) and 4077 (18.5%) were aged 80 years or older (39% men). Patients not previously diagnosed with CHF Box 2 shows the assessment process and results for the 22 060 patients. In the 4807 patients assessed as having possible CHF, at least one further investigation was performed in 2903 (60.4%). To determine whether the CASE audit itself may have prompted further investigation of these patients, the tests were divided into those ordered within the previous 12 months and those ordered subsequent to the CASE audit. Investigations ordered within the 12 months before the CASE audit were ECG in 1953 (40.6%), CXR in 1894 (39.4%), and echocardiogram in 366 patients (7.6%). Investigations subsequent to the CASE clinical assessment were performed in 488 patients who had ECGs (10.2%), 493 who had CXR (10.2%), and 466 who had echocardiograms (9.7%). The diagnosis of CHF was based on symptoms in 73%, signs in 66%, causative factors in 61%, and investigations in 49% (not mutually exclusive). Presence of at least one symptom and one causative factor had the highest sensitivity for detection of new heart failure (323 of the 420 [76.9%] new cases of heart failure). The sensitivity of the other diagnostic groupings for possible heart failure were > 2 symptoms, 68.6%; > 2 signs, 47.3%; > 1 symptom and > 1 sign, 68.6%; > 1 sign and > 1 causative factor, 66.9%. Possible false negative diagnoses: Of the 4807 patients who met diagnostic criteria for suspected CHF, 466 underwent echocardiography after the CASE audit (when systolic, diastolic or no dysfunction was specifically noted). Of these 466 patients, 108 had an echocardiographic report of left ventricular systolic or diastolic dysfunction. However, despite this objective evidence of ventricular dysfunction, GPs diagnosed CHF for only 77 of these 108 patients. Possible false positive diagnoses: Of the 420 patients newly diagnosed as having CHF, 162 underwent echocardiography. Nineteen of these 162 patients (11.7%) had no evidence of left ventricular systolic or diastolic dysfunction on this test, yet were still classified as having CHF by their GP. Patients previously diagnosed as having CHF CHF had been previously diagnosed in 2485 of the baseline population of 22 060 (11.3%). Both electrocardiograms and CXRs had been performed in 96% of the patients previously diagnosed as having heart failure, and 64% had had echocardiography performed. For these patients, in the previous 12 months: 1640 patients (66%) had been referred to a specialist; 1744 patients (70%) had either not been admitted to hospital with CHF or their hospitalisation status was unknown; and of the 741 patients admitted for CHF, 459 (62%) had one admission, 165 (22%) had two admissions, and 58 (8%) had three admissions. Six patients (1%) had been admitted 10 or more times for CHF. CHF patients in the CASE study At the end of the study, 2905 of the 22 060 baseline population (13.2%) were considered to have CHF: 2485 (11.2%) with a previous diagnosis, and 420 (1.9%) with a new diagnosis. The prevalence of CHF in these patients was closely related to age group (Box 3). The cardiovascular diagnoses that may be contributing to CHF in these patients are summarised in Box 4. Hypertension and ischaemic heart disease were major comorbidities and potential aetiological factors in both the new and previously diagnosed cohorts. Pharmacotherapy Specific CHF pharmacotherapy for the 2905 patients with CHF is summarised in Box 5. Most patients were receiving diuretics and ACE inhibitors. Alternatives to ACE inhibitors in patients who can not tolerate this medication include nitrates and hydralazine (prescribed for 0.6%) and/or angiotensin II receptor antagonists (prescribed for 4.3%). β-Blockers were prescribed for 12% of patients. Less than 50% of β-blocker prescribing was of the non-selective, vasodilating β-blocker carvedilol, approved for CHF in Australia. The dose of ACE inhibitor was determined in patients previously diagnosed as having CHF (Box 6). Based on our dosage equivalence table, prescribed doses were low in 60%, medium in 31%, and high in 9% of patients. Prescribing according to echocardiographic findings: Pharmacotherapy prescribed for CHF according to left ventricular (LV) systolic (found in 932 patients) or diastolic (found in 376 patients) dysfunction is summarised in Box 5. The presence of LV dysfunction on echocardiography resulted in higher prescribing of ACE inhibitors than in the overall patient cohort. However, the frequency of ACE inhibitor prescribing was not different between the systolic and diastolic LV dysfunction groups. Furthermore, there were very few differences among other agents in these groups according to systolic or diastolic LV dysfunction. Prescribing according to decade of life: Prescribing of drug therapy specifically for CHF according to decade of life is summarised in Box 5. ACE inhibitor prescribing was unaltered in the very elderly (≥ 80 years). Prescribing of β-blocker demonstrated an age-dependent decrease, whereas prescribing of digoxin and diuretics (thiazide and loop) demonstrated an age-dependent increase. Prescribing in patients with newly diagnosed CHF: Use of pharmacotherapy among newly diagnosed CHF patients was less than that observed in patients with previously diagnosed CHF. In particular, only 51% of newly diagnosed patients were prescribed ACE inhibitors, 37% diuretics, 17% received calcium-channel blockers, 10% digoxin and 8% β-blockers. Discussion We undertook a clinical algorithm approach to the possible diagnosis of CHF. By identifying possible CHF based on the grouping of symptoms, signs and causative factors, we demonstrated an 8.7% rate of identification of CHF (420 of 4807 patients). Although this approach resulted in a relatively low rate of successful diagnosis of CHF, the algorithm used was entirely clinical with a very simple screening process. Our results suggest that, of 100 patients aged 60 years or older presenting to a GP, two will have previously undetected CHF that can be simply diagnosed by attention to clinical symptoms and signs in conjunction with appropriate diagnostic tests. Prevalence of CHF We found somewhat higher rates of CHF patients (13.2%) than in earlier general practice based studies.4,7-9 Specifically, reported prevalence of CHF among patients aged 65 years or older in UK general practice ranged from 2.8%9 to 8.0%.7 The higher rate in the CASE study may reflect the differing methods by which the diagnosis of CHF was made (eg, patient file review,4,9 morbidity registry8), greater use of objective testing (ie, echocardiography in our patient cohort), or our study being a more representative sample of the true CHF population than previous geographically restricted studies performed in the US or UK. In contrast to the above assessments of CHF frequency, population studies where echocardiographic ventricular dysfunction was the main criterion for diagnosis detected fewer CHF patients within these age groups than in the CASE study.10,12 Numbers of CHF patients in the CASE Study increased dramatically with each decade of life — more than 20% of patients aged 80 years or older were diagnosed with CHF. Given the ageing of the population, these findings have important implications for resource allocation. Aetiology The aetiology of CHF was as expected, with a major contribution from ischaemic heart disease and previous myocardial infarction, as well as hypertension. Hypertension was a major contributor to CHF in the Framingham study,20,21 but less so in analysis of the Studies of Left Ventricular Dysfunction (SOLVD)22 and other, more recent data.23 The major contribution of hypertension in the CASE cohort may reflect the advanced age of the population studied, in which hypertension is a frequent comorbidity. Investigations Use of ECG and CXR was high, and echocardiography was used in more than half the patients. The lower use of echocardiography (despite recommendations by major organisations such as WHO)18 may reflect lack of full knowledge of the sensitivity and specificity of this diagnostic test, concerns regarding expense, and difficulty with access. Pharmacotherapy Use of ACE inhibitors: ACE inhibitor prescribing by Australian GPs ranges from 51%-71% of CHF patients, depending on the specific population studied. Prescribing of ACE inhibitor was more likely in patients in whom ventricular dysfunction had been objectively documented. These findings are consistent with international studies, in which prescribing of ACE inhibitors ranges from 10% to 60%.5,6,8-10,14-17 ACE inhibitors reduce morbidity and mortality across the entire spectrum of CHF severity, including in patients with asymptomatic systolic left ventricular dysfunction.24-26 Therefore, all patients with systolic left ventricular dysfunction should be receiving ACE inhibitors unless contraindicated or intolerant. Lack of compliance with these prescribing recommendations may relate to contraindications to ACE inhibitor therapy (ie, bilateral renal artery stenosis) or observed side effects such as hyperkalaemia or cough. Furthermore, ACE inhibitors are not of proven benefit in patients with diastolic CHF. Definitive diastolic dysfunction on echocardiography comprised only a small percentage in the CASE study, although the true percentage is undoubtedly considerably higher. Potential alternatives to ACE inhibitors in patients who are ACE intolerant or have contraindications include angiotensin II receptor antagonists and hydralazine (the latter as part of the hydralazine/nitrate combination). However, only 4.3% of patients were taking angiotensin II receptor antagonists and 0.6% were taking hydralazine. Our findings suggest that, despite the definitive data supporting the use of ACE inhibitors in CHF, these agents are still being underutilised. Dose of ACE inhibitors: Submaximal doses of ACE inhibitors were prescribed for those patients who are taking these drugs. The major clinical trials conducted in patients with CHF (SOLVD,24 CONSENSUS25) and LV dysfunction post-MI (SAVE27) used much higher doses (150 mg of captopril or 20-40 mg of enalapril) than the median and mean doses prescribed in this study. Doses prescribed by Australian GPs were generally lower than both the target and achieved ACE inhibitor doses used in these major trials. There are a number of reasons why the recommended target doses may not be achieved in general practice. First, patients may not tolerate the highest dosage because of hypotension, particularly if up-titration is rapid. Second, because these agents improve symptomatology, patients may become asymptomatic at lower doses of drug and the need to go to higher doses not be entertained in an asymptomatic patient. Finally, until recently, there has been no clear evidence that higher doses offer substantial clinical benefits over and above the use of ACE inhibitors at lower doses. The ATLAS study28 demonstrated a reduction in the combined endpoint of death/heart failure related hospitalisation with lisinopril 32.5-35 mg daily compared with lisinopril 2.5-5 mg daily. Mortality alone was reduced by 8% in the high-dose lisinopril subgroup. Although this reduction is modest, it does suggest that an attempt should be made to maximise ACE inhibitor dosage in every patient. β-Blockers: Prescribing of β-blockers was low, despite overwhelming evidence supporting the benefits of these agents in patients with New York Heart Association (NYHA) Class II-III symptoms.29-31 However, much of this evidence has only been published subsequent to the completion of the CASE study.30,31 Prescribing of the β-blocker vasodilator carvedilol occurred in fewer than half the patients receiving β-blockers. As carvedilol is the only β-blocker approved in Australia for CHF, this suggests that much of the prescribing of β-blockers for the CASE cohort was for indications other than CHF (eg, ischaemic heart disease and hypertension). As GPs in Australia are not permitted to prescribe carvedilol, our observed rate of use of β-blockers reflects specialist prescribing. Factors affecting prescribing: In patients with a definitive diagnosis of ventricular dysfunction by echocardiography, prescribing of ACE inhibitor therapy was higher than for the overall CASE CHF cohort. This may reflect more confidence with the cause of patient symptomatology as being related to CHF. Alternatively, it may be that a GP who is more likely to perform echocardiography to diagnose CHF is also more likely to prescribe best-practice pharmacotherapy. It was also noteworthy that the difference in overall prescribing for systolic versus diastolic dysfunction in these patients appeared similar, although many of the agents (eg, ACE inhibitors) are not of proven benefit in diastolic CHF. Furthermore, some drugs, such as non-dihydropyridine calcium-channel blockers, are relatively contraindicated in patients with systolic heart failure, yet prescribing rates were similar for the entire patient cohort. Conversely, these agents may be of particular benefit in diastolic heart failure, but again prescribing rates appeared similar to the entire patient cohort. There was no reduction in prescribing of ACE inhibitor with each decade of life, suggesting that GPs supported the use of these agents in CHF management in the very elderly (≥ 80 years). Very few data exist to support the use of ACE inhibitors in this group of patients, although studies are currently being conducted. In contrast, β-blocker use declined with each decade of life, suggesting less comfort in prescribing these agents for older patients. Increased digoxin and diuretic use with advanced age may reflect the need to increasingly prescribe these agents for comorbidities such as atrial fibrillation and oedema of other causes. Study limitations The CASE study had a number of potentially significant limitations. Selection of GPs was not random, but was based on interest in undertaking the study. This could introduce significant bias, and therefore we have not classified our evaluation as a prevalence or incidence study. Nevertheless, every effort was undertaken to ensure a representative distribution of general practices according to State, regional area and metropolitan versus rural practice. The study has also demonstrated the difficulty in making a clinical diagnosis of CHF. Diagnosis of CHF was left to the clinical judgement and decision of the GP. We noted a significant false positive and negative rate using documented left ventricular dysfunction on echocardiogram as the "gold standard" of CHF in conjunction with relevant signs, symptoms and causative factors. This is a limitation of many surveys of this type, in which the diagnosis is made based on subjective clinical criteria.4,9 A further limitation may have been the algorithm used to assist the GP in making the diagnosis. This clinical algorithm approach has not been used previously in the diagnosis of CHF. Therefore, the possibility exists of patients being wrongly assigned as having CHF using this approach. This is particularly true as echocardiography was not mandated for all patients. Nevertheless, this algorithm did yield an extra two new CHF patients for every 100 patients aged 60 years and older studied in this way. Acknowledgements The CASE study was supported by the National Heart Foundation of Australia and the Royal Australasian College of General Practitioners. The CASE Management Committee wish to thank all 341 GPs who participated in the CASE study and Servier Laboratories, Australia, who provided input into the study design as well as financial and logistical assistance in the conduct of the study. Servier Laboratories were not involved in the analysis of data. In addition, the Committee acknowledges the expert statistical assistance provided by Dr Chris Reid and Mr Stephen Lim (Baker Medical Research Institute, Prahran, VIC). References Bonneaux L, Barendregt J, Meeter K, et al. Estimating clinical morbidity due to ischemic heart disease and congestive heart failure: the future risk of heart failure. Am J Public Health 1994; 84: 20-28. Waters A-M, Bennett S. Mortality from cardiovascular disease in Australia. Cardiovascular Disease Series No. 3. Canberra: Australian Institute of Health and Welfare, 1995. McGovern PG, Pankow JS, Shahar E, et al. Recent trends in acute coronary heart disease. Mortality, morbidity, medical care and risk factors. N Engl J Med 1996; 334: 884-890. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993; 22: 6A-13A. Gardin JM, Siscovick D, AntonCulver H, et al. Sex, age and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly: the Cardiovascular Health Study. Circulation 1995; 91: 1739-1748. Lauer MS, Evans JC, Levy D. Prognostic implications of subclinical left ventricular dilatation and systolic dysfunction in men free of overt cardiovascular disease (the Framingham Heart Study). Am J Cardiol 1992; 70: 1180-1184. Mair FS, Crowley TS, Bundred P. Prevalence, aetiology and management of heart failure in general practice. Br J Gen Pract 1996; 46: 77-79. Morbidity statistics from general practice. 4th National Survey, 1991-92. Royal College of General Practitioners, Office of Population Census and Survey and Department of Health and Social Security. London: HMSO, 1995. Parameshwar J, Shackell MM, Richardson A, et al. Prevalence of heart failure in three general practices in west London. Br J Gen Pract 1992; 42: 287-289. McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 1997; 350: 829-833. Ambrosio GB, Riva LM, Casiglia E. Prevalence, clinical features and prognosis of congestive heart failure (CHF) in the elderly. A survey from a population in Veneto region. Acta Cardiologica 1994; 49: 324-325. Mosterd A, Bruijne de MC, Hoes AW, et al. Usefulness of echocardiography in detecting left ventricular systolic dysfunction in population based studies (The Rotterdam Study). Am J Cardiol 1997; 79: 103-104. Hillis GS, Trent RJ, Winton P, et al. Angiotensin-converting enzyme inhibitors in the management of congestive heart failure: are we ignoring the evidence? Q J M 1995; 89: 145-150. Mosterd A, Hoes AW, de Bruijne MC, et al. Prevalence of heart failure and (a) symptomatic left ventricular dysfunction in the general population. The Rotterdam Study. Eur Heart J 2001; in press. Bart BA, Gattis WA, Diem SJ, O'Connor CM. Reasons for underuse of angiotensin-converting enzyme inhibitors in patients with heart failure and left ventricular dysfunction. Am J Cardiol 1997; 79: 1118-1120. Newman J, Ahmed O, Hyngstrom T, et al. Heart failure treatment with angiotensin converting enzyme inhibitors in hospitalized Medicare patients in 10 large states. Arch Int Med 1997; 157: 1103-1108. Stafford RS, Saglam D, Blumenthal D. National patterns of angiotensin converting enzyme inhibitor use in congestive heart failure. Arch Intern Med 1997; 157: 2460-2464. World Health Organization/Council on Geriatric Cardiology Task Force on Heart Failure Education. Concise guide to the management of heart failure. Geneva: WHO/CGC, 1997; 6-9. Available at <http://www.who.int/ncd/cvd/concguid.pdf>. Rural, remote and metropolitan areas classification. 1991 Census Edition. Canberra: AGPS, 1994. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham Study. N Engl J Med 1971; 285: 1441-1446. Kannel WB, Belanger JA. Epidemiology of heart failure. Am Heart J 1991; 121: 951-956. Bangdiwala SI, Weiner DH, Bourassa MG, et al. Studies of Left Ventricular Dysfunction (SOLVD) Registry: rationale, design, methods and description of baseline characteristics. Am J Cardiol 1992; 70: 347-353. Teerlink JR, Goldhaber SZ, Pfeffer MA. An overview of contemporary etiologies of congestive heart failure. Am Heart J 1991; 121: 1852-1853. The SOLVD Investigators. Effect of Enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991; 325: 293-302. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 3161: 1429-1435. Nicklas JM, Pitt B, Timmis G, et al. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685-691. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992; 327: 821-828. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100: 2312-2318. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349-1355. CIBIS II investigators and committees. The cardiac insufficiency bisoprolol study II (CIBIS II): a randomised trial. Lancet 1999; 353: 9-13. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001-2007. (Received 24 Dec 1999, accepted 28 Oct 2000) Authors' details Alfred Hospital, Melbourne, VIC. Henry Krum, PhD, FRACP, Associate Professor, Clinical Pharmacology Unit, Department of Epidemiology and Preventive Medicine, and Department of Medicine, Monash University. National Heart Foundation of Australia, Melbourne, VIC. Andrew M Tonkin, MD, FRACP, Director, Health, Medical and Scientific Affairs. North East Valley Division of General Practice, Melbourne, VIC. Robert Currie, MB BS, FRACGP, Director. Servier Laboratories, Melbourne, VIC. Robert Djundjek, BSc, Manager, Scientific Projects. Austin and Repatriation Medical Centre, Melbourne, VIC. Colin I Johnston, MD, FRACP, Professor and Head, Department of Medicine, University of Melbourne. Reprints will not be available from the authors. Correspondence: Professor C I Johnston, Baker Medical Research Institute, Prahran, VIC 3181. Make a comment 1: Modified World Health Organization18 criteria for assessment of possible chronic heart failure Symptoms: Dyspnoea, chronic fatigue, oedema, and exercise intolerance. Signs: Third or fourth heart sounds, heart murmur, cardiomegaly, pulmonary crackles, raised jugular venous pressure, and dependent oedema. Causative factors: Angina, previous myocardial infarction, hypertension, valvular heart disease/rheumatic fever, and cardiomyopathy. Patients were considered to have possible CHF if they had: > 2 symptoms, > 2 signs, > 1 symptom and > 1 sign, or > 1 symptom and > 1 causative factor. Back to text Back to text Back to text 4: Cardiovascular comorbidities that may be contributing to chronic heart failure Percentage of patients New CHF Previous CHF Hypertension 69.1% 63.6% Angina 44.2% 53.4% Previous MI 28.1% 39.3% Valve disease 15.2% 23.0% Cardiomyopathy 5.2% 11.8% MI = myocardial infarction. Back to text 5: Percentage (95% CI) of patients with chronic heart failure prescribed each class of drug, by evidence of left ventricular dysfunction, and by age group Left ventricular dysfunction* All patients (n = 2905) Systolic (n = 932) Diastolic (n = 376) Diuretics (thiazide, loop) 63.3 (62.4-64.2) 60.3 (58.7-61.9) 62.2 (59.7-64.7) ACE inhibitor 58.1 (57.2-59.0) 70.7 (69.2-72.2) 70.5 (68.1-72.9) Digoxin 31.3 (30.4-32.2) 35.0 (33.4-36.6) 33.2 (30.8-35.6) beta-Blocker 11.8 (11.2-12.4) 13.9 (12.8-15.0) 17.8 (15.8-19.8) CCB-DHP 10.1 (9.5-10.7) 11.1 (10.1-12.1) 12.0 (10.3-13.7) CCB-NDHP 10.0 (9.4-10.6) 10.3 (9.3-11.3) 11.2 (9.6-12.8) Aspirin 10.3 (9.7-10.8) 9.3 (8.3-10.3) 9.6 (8.1-11.1) Warfarin 7.7 (7.2-8.2) 8.2 (7.3-9.1) 8.8 (7.3-10.3) Spironolactone 8.1 (7.6-8.6) 6.9 (6.1-7.7) 1.0 (0.5-1.5) Hydralazine 0.6 (0.5-0.7) 0.2 (0.1-0.3) 0.0 (0.0-0.0) AIIA 4.3 (3.9-4.7) 6.4 (5.6-7.2) 7.7 (6.3-9.1) Age group (years) 60-69 (n = 569) 70-79 (n = 1360) ≥80 (n = 976) Diuretics (thiazide, loop) 57.1 (55.0-59.2) 62.1 (60.8-63.4) 68.4 (66.9-69.9) ACE inhibitor 58.7 (56.6-60.8) 58.0 (56.7-59.3) 58.1 (56.5-59.7) Digoxin 24.8 (23.0-26.6) 29.9 (28.7-31.1) 37.2 (35.7-38.7) beta-Blocker 14.1 (12.6-15.6) 13.2 (12.3-14.1) 8.4 (7.5-9.3) CCB-DHP 9.5 (8.3-10.7) 11.0 (10.2-11.8) 9.0 (8.1-9.9) CCB-NDHP 10.2 (8.9-11.5) 11.0 (10.2-11.8) 11.2 (10.2-12.2) Aspirin 10.0 (8.7-11.3) 11.4 (10.5-12.3) 8.9 (8.0-9.8) Warfarin 9.5 (8.3-10.7) 8.8 (8.0-9.6) 5.0 (4.3-5.7) Spironolactone 6.7 (5.7-7.7) 8.8 (8.0-9.6) 8.0 (7.1-8.9) Hydralazine 1.1 (0.7-1.5) 0.6 (0.4-0.8) 0.3 (0.1-0.5) AIIA 3.5 (2.7-4.3) 5.4 (4.8-6.0) 3.4 (2.8-4.0) * According to echocardiography. ACE = angiotensin-converting enzyme. CCB-DHP = calcium-channel blocker - dihydropyridine. CCB-NDHP = calcium-channel blocker - non-dihydropyridine. AIIA = angiotensin II receptor antagonist. Back to text 6: Dosage equivalence table for angiotensin-converting enzyme (ACE) inhibitors, and median and mean doses prescribed for patients with diagnosed chronic heart failure Dosage equivalence (mg) Low Medium High Captopril ≤ 50 ≤ 100 ≤ 150 Enalapril ≤ 10 ≤ 20 ≤ 40 Perindopril ≤ 2 ≤ 4 ≤ 8 Lisinopril ≤ 10 ≤ 20 ≤ 40 Ramipril ≤ 5 ≤ 10 ≤ 20 Fosinopril ≤ 10 ≤ 20 ≤ 40 Trandolopril ≤ 2 ≤ 4 ≤ 8 Quinapril ≤ 10 ≤ 20 ≤ 40 Dose (mg) Media Mean SD n Captopril 50 67.5 44.1 383 Enalapril 10 15.6 12.0 308 Perindopril 4 3.6 2.2 223 Lisinopril 10 12.6 9.7 218 Ramipril 5 5.1 4.3 98 Fosinopril 10 14.3 7.1 81 Trandolopril 1 1.9 1.8 76 Quinapril 10 11.6 9.1 74 Back to text

Henry Krum · Andrew M Tonkin · Robert Currie · Robert Djundjek · Colin I Johnston

Note: This document has now been superseded by the 2006 edition. Click here to access the 2006 edition. Abstract Chronic heart failure (CHF) affects approximately 1% of people aged 50-59 years, and this high prevalence increases dramatically with age. CHF is a common reason for hospital admission and general practitioner consultation in the elderly. Common causes of CHF are ischaemic heart disease, hypertension and idiopathic dilated cardiomyopathy. Diagnosis of CHF is based on clinical features and objective measurement of ventricular function (eg, echocardiography). Management is directed at prevention, retarding disease progression, relief of symptoms and prolonging survival. Non-pharmacological approaches include exercise, home-based support and risk-factor modification. Angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of pharmacological therapy to prevent disease progression and prolong survival. ß-Blockers prolong survival when added to ACE inhibitors in symptomatic patients. Diuretics provide symptom relief and restoration or maintenance of euvolaemia. Spironolactone, angiotensin II receptor antagonists and digoxin may be useful in some patients. Surgical approaches in highly selected patients may include myocardial revascularisation, insertion of devices and cardiac transplantation. Most of the current information on the epidemiology of chronic heart failure (CHF) is derived from seven major overseas epidemiological studies published since 1985.1 There have been several consistent findings, including a sharp increase in prevalence with age and a marked male preponderance.2 The prevalence of CHF is approximately 1% in people aged 50 to 59 years, but over 50% in people 85 years and older. Information on the overall incidence and prevalence of CHF in Australia is derived mainly by extrapolation of overseas information. Based on data from the United States,3 it is likely that at least 300 000 Australians are affected with CHF and about 30 000 new cases are diagnosed annually. There are more reliable Australian data regarding hospitalisation for CHF -- in 1996 and 1997, 41 000 hospitalisations reported CHF as a principal diagnosis, and CHF accounted for 0.8% of all hospitalisations in Australia in these two years, with patients aged 70 years and over accounting for over three-quarters of all hospitalisations for CHF. During 1996 and 1997, CHF contributed 2% of all deaths.4 CHF also constitutes a common reason for consultations with general practitioners. A recent survey of 341 Australian general practitioners estimated that, for every 100 patients aged 60 years and over seen in general practice, 11 had known CHF and two would be newly diagnosed as having CHF based on clinical features and known aetiological factors.5 The cost burden associated with CHF is expected to increase markedly6 because of a number of factors, including: ageing of the population; the projected increase in the number of older people with coronary heart disease and hypertension; the decrease in case-fatality rates associated with acute coronary syndromes; and improved diagnosis of CHF because of increased use of sensitive techniques, such as echocardiography. There are no precise data for Australia relating to the economic burden associated with CHF. However, direct health costs for cardiovascular disease in 1993-94 were estimated at $3719 million (12% of total health care costs), and CHF has been estimated to account for $411 million of these costs, including $140 million per annum for costs of hospitalisation and $135 million per annum for nursing home costs. Causes and diagnosis Although systolic and diastolic CHF often coexist, the distinction between them is relevant to the therapeutic approach. Causes of chronic heart failure are shown in Box 1. Diagnosis is based on well-known clinical features and appropriate investigations, not only to confirm or exclude the diagnosis of CHF, but also to establish underlying causes for which particular treatment is necessary. Recommendations relating to the diagnosis of CHF are shown in Box 2. Management of chronic heart failure General non-pharmacological measures are important in the management of CHF and are summarised in Box 3, and recommendations for therapy in asymptomatic patients or to prevent CHF are summarised in Box 4. Details supporting the use of drugs in systolic CHF are summarised in Box 5 and the management of diastolic CHF is summarised in Box 6. Angiotensin-converting enzyme (ACE) inhibitors Because of the major importance of renin-angiotensin system activation in the progression of CHF, blockade of this system has become the cornerstone of successful therapy for systolic ventricular dysfunction. ACE inhibitors have been shown to: prolong survival (compared with placebo) in patients with New York Heart Association Class II, III and IV CHF;31,32 improve patient symptom status, exercise tolerance and reduce hospitalisation for worsening CHF45 (in some but not all studies); and increase ejection fraction compared with placebo in many studies. The optimal dose of ACE inhibitor has not been definitively determined. In one study that examined ACE inhibitor dosage, there was no difference in the combined endpoint of death, CHF hospitalisation or worsening CHF whether enalapril was used at 2.5 mg, 5 mg or 10 mg twice daily.46 In a study comparing lisinopril at doses of 2.5-5 mg and 32.5-35 mg daily, there was a marginal, non-significant reduction in mortality, with a significant but rather small (12%) reduction in the combined endpoint of death and all-cause hospitalisation with the higher dose.34 These data have been interpreted in many ways, but there is general agreement that all patients with CHF should be established on therapy with at least low doses of ACE inhibitors, and that an effort should be made to up-titrate to higher doses if possible. ß-Blockers As with ACE inhibitors, ß-blockers inhibit the adverse effects of chronic activation of a key neurohormonal system (in this case, the sympathetic nervous system) on the myocardium. These adverse actions may be mediated via ß1-receptors, ß2-receptors, and/or α1-receptors. Three ß-blockers — carvedilol (ß1-, ß2- and α1-antagonist),35 bisoprolol (ß1-selective antagonist, not currently available in Australia)36 and metoprolol extended release (ß1-selective antagonist, formulation not currently available in Australia)37 — have been shown to prolong survival in patients with mild to moderate CHF already receiving background ACE inhibitor therapy. More recently, carvedilol has been shown to prolong survival (35% relative reduction in risk of death)39 in a prospective study of patients with severe CHF symptoms who did not have overt volume overload or recent acute decompensation. Similar observations have been made from post-hoc analyses of subgroups with advanced heart failure symptoms in the above trials of metoprolol and bisoprolol. ß-Blocker therapy should not be initiated during a phase of decompensation, but only after the patient's condition has stabilised. ß-Blockers should be started at very low initial doses, then up-titrated slowly to target dose, with the expectation that it may take some months before clinical benefits occur. Adverse effects of initiation of ß-blockade in CHF are commonly observed and include symptomatic hypotension, worsening of underlying disease because of withdrawal of sympathetic drive, and bradycardia. However, side effects are usually transitory and rarely necessitate cessation of ß-blocker therapy. Patients with minimal symptoms (New York Heart Association Class II) derive little symptomatic benefit from ß-blocker therapy,47 while clinically significant improvements in symptom status are observed in those with more advanced disease. Symptomatic benefit is delayed with ß-blockade, and this may be an important issue in decision-making about starting the drug in severely symptomatic patients with limited life expectancy. Diuretics Diuretics are used to improve symptoms. They have been shown to increase urine sodium excretion and to decrease the physical signs of fluid retention in patients with CHF, thus rapidly improving symptom status. In patients with fluid overload, the aim is to achieve an increase in urine output and weight reduction of 0.5-1 kg daily, generally with loop diuretics, until euvolaemia (evaluated from clinical symptoms and signs as well as the patient's bodyweight) is achieved. Combined use of loop and thiazide diuretics is often used in clinical practice, although objective data supporting this combination are limited. The dose of diuretic should be regularly reassessed, as dosage may need to be adjusted based on whether the patient is considered to be volume overloaded or underloaded on clinical evaluation. Spironolactone Although traditionally considered a potassium-sparing loop diuretic, spironolactone has a number of other potential properties that make it an important agent in the treatment of CHF. Aldosterone receptors within the heart mediate fibrosis, hypertrophy and arrhythmogenesis. Thus, blockade of these receptors with spironolactone may theoretically provide benefit in CHF. This hypothesis has recently been supported by the observation of a 30% reduction in all-cause mortality and symptomatic improvement in advanced CHF patients receiving spironolactone (average, 25 mg per day) compared with placebo.40 The risk of the potentially lethal adverse effect of hyperkalaemia, particularly in the setting of concomitant renin-angiotensin system blockade and/or renal impairment, makes careful monitoring mandatory when using spironolactone. Digitalis The cardiac glycoside digoxin acts to inhibit sodium-potassium ATPase in patients with ventricular dysfunction; blockade of this enzyme has been associated with improved inotropic responsiveness. Digoxin may also sensitise cardiopulmonary baroreceptors, reduce central sympathetic outflow, increase vagal activity and has been shown to reduce renin secretion. There have been a number of studies in patients with CHF and sinus rhythm that support the favourable effect of digoxin on symptoms and ejection fraction. Withdrawal of digoxin in the presence of an ACE inhibitor leads to progressive clinical deterioration in symptom status as well as exercise tolerance.42 In contrast, the only placebo-controlled trial of mortality with digoxin yielded a neutral outcome.43 While deaths from worsening CHF were reduced with digoxin therapy, this was offset by an increase in sudden deaths. However, digoxin therapy was accompanied by a reduction in hospitalisation for worsened CHF and patients with more severe symptoms appeared to benefit symptomatically from the introduction of digoxin. Digoxin remains valuable therapy in CHF patients with concomitant atrial fibrillation (AF). Other drugs Hydralazine and isosorbide dinitrate — This combination of vasodilator drugs has shown marginal superiority compared with placebo in terms of overall mortality,48 and no benefit for hospitalisation. The ACE inhibitor enalapril was clearly shown to be superior to hydralazine and isosorbide dinitrate by reducing sudden deaths.44 Angiotensin II receptor antagonists — It is uncertain whether angiotensin II (AII) receptor antagonists offer additional benefits over ACE inhibitors. They are generally better tolerated than ACE inhibitors because they do not produce kinin-mediated side effects, such as dry cough. On the other hand, inhibition of kinin breakdown by ACE inhibitors may be an important component of their beneficial mechanism (ie, bradykinin-induced nitric oxide synthesis). Comparative studies of ACE inhibitors versus AII antagonists have tested these hypotheses,49,50 but have shown no evidence for superiority of AII receptor antagonists; indeed, there was a significant mortality benefit with the combination of ACE inhibitor and ß-blocker compared with the AII receptor antagonist and ß-blocker combination.50 It is possible (but not yet confirmed) that combination therapy with ACE inhibitors and AII antagonists may maximise the benefits of renin-angiotensin system blockade.41 There may also be an adverse interaction of this combination with ß-blockers.41 Based on the above findings, AII receptor antagonists may be considered as an alternative to ACE inhibitors for patients who are truly ACE-inhibitor intolerant as a result of kinin-mediated adverse effects such as cough.41 Drugs to avoid in chronic heart failure Anti-arrhythmic agents (apart from ß-blockers and amiodarone) should be avoided because of their pro-arrhythmic potential, negative inotropic effects, and a tendency to increase mortality. Calcium antagonists that are direct negative inotropic agents, such as verapamil and diltiazem, are absolutely contraindicated in patients with systolic CHF. Dihydropyridine calcium antagonists such as amlodipine and felodipine offer no survival benefit in systolic CHF.51-53 Tricyclic antidepressants should be avoided because of their pro-arrhythmic potential. Non-steroidal anti-inflammatory drugs (NSAIDs)54 should be avoided, as they can inhibit the effects of diuretics and ACE inhibitors and can worsen both cardiac and renal function. Cyclooxygenase (COX)-2 inhibitors appear to have similar adverse effects on salt and water retention as do standard NSAIDs.55 Pharmacological therapies reserved for advanced chronic heart failure Positive inotropic agents can improve cardiac performance during short-term and long-term therapy. -Adrenergic agonists (eg, dobutamine) and phosphodiesterase inhibitors (eg, milrinone) enhance cardiac contractility by increasing myocardial levels of cyclic adenosine monophosphate. However, despite favourable short-term haemodynamic and clinical effects, long term oral therapy with positive inotropic agents has not been shown to reliably improve symptoms or clinical status and has been associated with a significant increase in mortality.56-58 For similar reasons, long term intermittent infusions of positive inotropic therapy are not recommended. A small proportion of patients can not be weaned from inotropes despite repeated attempts, but are well enough with inotrope therapy to be managed at home with the aid of a portable pump and long-term IV access. This can be used as a bridging strategy to heart transplantation, or as palliation. Treatment of associated disorders CHF and cardiac arrhythmia Efforts should be made to restore and maintain sinus rhythm in patients with atrial fibrillation (AF). This may require episodic electrical cardioversion while patients are anticoagulated with warfarin. If sinus rhythm can not be maintained for prolonged periods, therapy should be directed at controlling the ventricular response rate (with digoxin, -blockers or amiodarone) and reducing thromboembolic risk by anticoagulation with warfarin.59 Use of amiodarone should be considered in patients who have frequent episodes of symptomatic ventricular tachycardia (VT), and as a component of therapy in patients at high risk of ventricular fibrillation (VF). Therapy with Class I anti-arrhythmic agents (eg, flecainide) is generally contraindicated in the presence of systolic CHF. CHF and ischaemic heart disease Specific treatment of ischaemia may represent the primary therapeutic option in selected patients presenting with symptoms of CHF. CHF patients with demonstrably reversible ischaemia should be considered for myocardial revascularisation procedures. Calcium antagonists should generally be avoided as anti-anginal therapy in patients with left ventricular ejection fractions below 40%. -Blockers represent a major component of anti-anginal therapy in CHF, and should be used whenever tolerated. Prophylactic nitrate therapy should usually be a component of anti-anginal therapy in CHF. Patients with severe angina and inoperable disease, together with systolic CHF, may be considered for prophylactic therapy with perhexiline, as long as plasma drug levels are monitored regularly to prevent toxicity. CHF and arthritis CHF patients with severe systolic dysfunction, hyponatraemia, or both, should not be treated with large doses of COX inhibitors (both non-selective and COX-2-selective) for arthritis, as these drugs will increase the risk of worsening CHF.54,55Low-dose aspirin (up to 150 mg/day) appears to be well tolerated in patients with CHF. Higher doses should probably be avoided.60 There is controversy at present about a possible interaction between aspirin and ACE inhibitors which might decrease the efficacy of the ACE inhibitors.61 Ancillary therapies Pacing Pacing may be needed to treat symptomatic bradyarrhythmias. Whenever possible, atrioventricular synchrony should be maintained in view of the significant contribution of atrial filling to cardiac output in CHF. Upgrading a ventricular pacemaker to a dual-chamber device should be considered in patients with CHF who have electrocardiographic evidence of organised atrial activity. Rate-responsiveness may also be a useful pacing characteristic in CHF patients. The use of biventricular pacing to resynchronise cardiac contraction in patients with systolic CHF and left bundle branch block is currently the subject of several international trials. Results so far are promising, with symptomatic benefit in patients programmed in biventricular mode.62 Longer-term and mortality data are awaited. Surgery (other than revascularisation) Surgical management of mitral regurgitation can produce significant improvement in both symptoms and left ventricular function. Left ventricular aneurysmectomy may benefit patients with CHF in whom a large aneurysm can be excised, particularly if the remaining myocardium is functionally normal and there is minimal residual coronary artery disease. Left ventricular free wall excision (frequently with concomitant mitral valve repair or replacement) aims to restore a normal myocardial mass-to-volume ratio in patients with severe left ventricular dilatation. This procedure has not yet been subjected to the clinical trials needed to define its place (if any) in managing CHF.63 Cardiomyoplasty via stimulated skeletal muscle wraps has been used to augment the function of the failing left ventricle in patients with New York Heart Association Class III symptoms and only modest left ventricular dilatation.64 Because of disappointing results with this approach, non-stimulated synthetic wraps, which passively restrict LV dilatation, have more recently been evaluated, with promising initial results.65 Left ventricular assist devices (LVADs) are most often used as a temporary bridge to cardiac transplantation or for recovery of the heart after cardiac surgery.66 While they have occasionally been used as a long-term alternative to cardiac transplantation, no device is approved for this indication. The prohibitive cost, large size, the fact that only part of the device is implantable and risk of complications (especially infection and thromboembolism) limit the widespread use of currently available LVADs in patients with end-stage CHF. Cardiac transplantation is an accepted therapy for certain patients with refractory CHF who meet eligibility criteria.67 The five-year survival is 65%-75%, but a shortage of donors means it is available only for a very small subset of patients. Diastolic heart failure Diastolic heart failure is common and may account for up to 40% of patients with heart failure. A proposed schema for management of diastolic heart failure is summarised in Box 6. It is important to note that these recommendations for therapy represent expert opinion only, as no randomised controlled trial has yet been completed with any agent specifically for diastolic CHF. Disclosure Many members of the Writing Panel have received paid honoraria for work performed on behalf of manufacturers of therapies described in these guidelines. However, no members of the Writing Panel stand to gain financially from their involvement in these guidelines and no conflicts of interest exist for Writing Panel members, the National Heart Foundation or the Cardiac Society of Australia & New Zealand. Reference Yamani M, Massie BM. Congestive heart failure: insights from epidemiology, implications for treatment. Mayo Clin Proc 1993; 68: 1214-1218. Kannel WB, Cupples A. Epidemiology and risk profile of cardiac failure. Cardiovasc Drugs Ther 1988; 2 Suppl 1: 387-395. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285: 1441-1446. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases, Australian facts. Canberra: AIHW and Heart Foundation of Australia, 1999. (AIHW Catalogue no. CVD 7; Cardiovascular Disease Series No.10.) Krum H, Tonkin AM, Currie R, et al. Frequency, awareness and pharmacological management of chronic heart failure in Australian general practice. The Cardiac Awareness Survey and Evaluation (Case) Study. Med J Aust 2001; 174: 439-444. Kelly DT. Paul Dudley White international lecture. Our future society. A global challenge. Circulation 1997; 95: 2459-2464. Mancini DM, Walter G, Reichek N, et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992; 85: 1364-1373. Coats AJS, Adamopolous S, Meyer TE, et al. Effects of physical training in chronic heart failure. Lancet 1990; 335: 63-66. Bellardinelli R, Georgiou D, Cianci G, et al. Randomised, controlled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, capacity, quality of life, and clinical outcome. Circulation 1999; 99: 1173-1182. Keteyian SJ, Levine AB, Brawner CA, et al. Exercise training in patients with heart failure. A randomised, controlled trial. Ann Intern Med 1996; 124: 1051-1057. Rich MW, Beckham V, Wittenberg C, et al. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995; 333: 1190-1195. Stewart S, Vandenbroek A, Pearson S, et al. Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure. Arch Intern Med 1999; 159: 257-261. Naughton MT. Impact of treatment of sleep apnoea on left ventricular function in congestive heart failure. Thorax 1998; 53 Suppl 3: S37-S40. McDonald CD, Burch GE, Walsh JJ. Prolonged bed rest in the treatment of idiopathic cardiomyopathy. Am J Med 1972; 52: 41-50. The National Heart Foundation of New Zealand, Cardiac Society of Australia and New Zealand and the Royal New Zealand College of General Practitioners Working Party. New Zealand guidelines for the management of chronic heart failure. N Z Med J 1997; 110: 99-107. The Task Force of the Working Group on Heart Failure of the European Society of Cardiology. The treatment of heart failure. Eur Heart J 1997; 18: 736-753. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC 1999. Nicklas JM, Pitt B, Timmis G, et al. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685-691. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992; 327: 669-677. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145-153. Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA 1997; 278: 212-216. MRC Working Party Medical Research Council. Trial of treatment in older adults: principal results. BMJ 1992, 304: 405-412. Dahlof B, Lindholm JH, Hansson L, et al. Morbidity and mortality in the Swedish trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991, 338: 1281-1285. Hansson L, Lindholm LH, Niskanen L, et al. Principal results of the Captopril Prevention Project (CAPP) randomised trial. Lancet 1999, 353: 611-616. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the international nifedipine GITS study: intervention as a goal in hypertension treatment. Lancet 2000; 356: 366-372. Hansson L, Hedner T, Lund-Johansen P, et al Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359-365. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA 1997; 277: 739-745. Dargie HJ. Design and methodology of the CAPRICORN trial -- a randomised double blind placebo controlled study of the impact of carvedilol on morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail 2000; 2: 325-332. Freemantle N, Cleland JGF, Young P, et al. Beta-blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999; 318: 1730-1777. Kjekshus J, Pedersen TR, Olsson AG, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997; 3: 249-254. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991; 325: 293-302. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429-1435. Armstrong PW, Moe GW. Medical advances in the treatment of congestive heart failure. Circulation 1993; 88: 2941-2952. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100: 2312-2318. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349-1355. CIBIS II investigators and committees. The cardiac insufficiency bisoprolol study II (CIBIS II): a randomised trial. Lancet 1999; 353: 9-13. MERIT Investigators. Effect of metoprolol CR/XL in chronic heart failure. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001-2007. Carson PE. Beta-blocker treatment of heart failure. Prog Cardiovasc Dis 1999; 41: 301-321. Packer M, Coats AJS, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the survival of patients with severe chronic heart failure. New Engl J Med 2001. In press. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709-717. Thackray SD, Witte KK, Khand A, et al. Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure. Eur J Heart Fail 2001; 3: 117-124. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993; 329: 1-7. Digitalis Intervention Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525-533. Cohn JN, Johnson G, Ziesche S, et al A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-310. Pflugfelder PW, Baird MG, Tonkon MJ, et al. Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind placebo-controlled study of quinapril. J Am Coll Cardiol 1993; 22: 1557-1563. The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. Eur Heart J 1998; 19: 481-489. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997; 349: 375-380. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314: 1547-1552. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997; 349: 747-752. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial — the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582-1587. Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on survival. Evaluation Study Group. N Engl J Med 1996; 335: 1107-1114. Thackray S, Witte K, Clark AL, Cleland JG. Clinical trials update: OPTIME-CHF, PRAISE-2, ALL-HAT. Eur J Heart Fail 2000; 2: 209-212. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997; 96: 856-863. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000; 160: 777-784. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med 2000; 133: 1-9. Packer M, Carver JR, Rodeheffer RJ, et al, for the PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991; 325: 1468-1475. Hampton JR, van Veldhuisen DJ, Kleber FX, et al, for the Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Lancet 1997; 349: 971-977. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1-6. Mackstaller LL, Alpert JS. Atrial fibrillation: a review of mechanism, etiology, and therapy. Clin Cardiol 1997; 20: 640-650. Cleland JG, Bulpitt CJ, Falk RH, et al. Is aspirin safe for patients with heart failure? Br Heart J 1995; 74: 215-219. Hall D. The aspirin-angiotensin-converting enzyme inhibitor tradeoff: to halve and halve not. J Am Coll Cardiol 2000; 35: 1808-1812. Barold SS. Biventricular cardiac pacing : promising new therapy for congestive heart failure. Chest 2000; 118: 1819-1812. Dreyfus G, Mihealainu S. The Batista procedure. Heart 2001; 85: 1-2. Jessup M. Dynamic cardiomyoplasty: expectations and results. J Heart Lung Transplant 2000; 19 (8 Suppl): S68-S72. Raman JS, Power JM, Buxton BF, et al. Ventricular containment as an adjunctive procedure in ischemic cardiomyopathy: early results. Ann Thorac Surg 2000; 70: 1124-1126. Jaski BE, Lingle RJ, Reardon LC, Dembitsky WP. Left ventricular assist device as a bridge to patient and myocardial recovery. Prog Cardiovasc Dis 2000; 43: 5-18. Dabol R, Edwards NM. Cardiac transplantation and other therapeutic options in the treatment of end-stage heart disease. Compr Ther 2000; 26: 109-113. Authors' details National Heart Foundation of Australia, Melbourne, VIC. Henry Krum, MB BS, PhD, Associate Professor, Department of Epidemiology and Preventive Medicine, and Department of Medicine, Monash University, Alfred Hospital, Melbourne, VIC. Correspondence: Associate Professor H Krum, Clinical Pharmacology Unit, Department of Epidemiology and Preventive Medicine, and Department of Medicine, Monash University, Alfred Hospital, Prahran, 3181 VIC. henry.krumATmed.monash.edu.au * See background and evidence basis of recommendations box at the end of the article. Background and evidence basis of recommendations This article is a summary of evidence-based clinical practice guidelines on the best practice management of chronic heart failure (CHF) in the Australian setting recently developed by the National Heart Foundation of Australia (NHF) and the Cardiac Society of Australia & New Zealand (CSANZ). Financial and administrative support was drawn from both organisations. These guidelines were written by a multi-disciplinary panel comprising Associate Professor Henry Krum (Chair); Professor Andrew Tonkin (NHF); Associate Professor Michael Jelinek (CSANZ); Dr Mark Harris (Royal Australian College of General Practitioners); Professor John McNeil, Dr David Hunt, Dr David Kaye, Associate Professor Louise Burrell, Associate Professor Leonard Arnolda, Associate Professor Anne Keogh, Dr Peter Bergin, Dr Warren Walsh, Associate Professor Andrew Sindone, Dr David Hare, Ms Di Holst, Dr Gerry O'Driscoll, Professor John Horowitz, Dr Meroula Richardson, Dr Julian Smith, Dr Phil Spratt, Professor Leon Piterman, Dr Ian Cameron, Associate Professor Peter Macdonald, Dr Andrew Galbraith, Dr Alan Henderson, Ms Kylie Oliver, Dr Peter Martin; Mr Gerry Atkinson (Heart Support Australia); Ms Bev Motteram (Cardiomyopathy Association of Australia); Ms Helen Egan (NHF Program Manager); Dr Jacinta Halloran (medical writer). These guidelines were externally reviewed by the European Society of Cardiology Working Group on Heart Failure, American College of Cardiology/American Heart Association, Royal Australasian College of Physicians, Royal Australasian College of General Practitioners and New Zealand Guidelines Group. The aim was to develop recommendations towards achieving the best health outcomes for people with CHF. Current relevant literature was reviewed, with assessment of the quality of evidence for each recommendation adapted from the NHMRC 1999 Designation of Levels of Evidence.17 1: Causes of chronic heart failure Systolic (impaired ventricular contraction) Common causes: Ischaemic heart disease and prior myocardial infarction Hypertension Less common causes: Non-ischaemic idiopathic dilated cardiomyopathy Uncommon causes: Valvular heart disease Alcoholic cardiomyopathy Inflammatory cardiomyopathy, or myocarditis (traditionally associated with a history of viral infections such as enteroviruses, especially Coxsackie B virus) HIV-related cardiomyopathy Drug-induced cardiomyopathy, especially anthracyclines (eg, daunorubicin and doxorubicin, cyclophosphamide, paclitaxel and mitoxantrone) Peripartum cardiomyopathy Chronic arrhythmia Diastolic (impaired ventricular relaxation) Common causes: Hypertension Ischaemic heart disease Less common causes: Valvular disease, especially aortic stenosis Uncommon causes: Hypertrophic cardiomyopathy Restrictive cardiomyopathy 2: Recommendations for diagnosis of chronic heart failure (CHF) Level of evidence All patients with suspected CHF should have an objective measurement of ventricular function, preferably by transthoracic echocardiography EO Coronary angiography should be considered in patients with CHF who have a history of exertional angina or suspected ischaemic left ventricular dysfunction EO Haemodynamic measurements may be particularly helpful in patients with refractory CHF, recurrent diastolic CHF or in whom the diagnosis of CHF is in doubt EO Endomyocardial biopsy may be indicated in patients with cardiomyopathy with recent onset of symptoms, in whom coronary artery disease has been excluded by angiography, or in whom systolic ventricular dysfunction is suspected EO Nuclear cardiological testing, stress echocardiography and positron emission tomography can all be used to assess reversibility of ischaemia and viability of myocardium in CHF patients with myocardial dysfunction and coronary disease EO Thyroid function tests should be considered, especially in older patients who develop atrial fibrillation, and who have pre-existing heart disease EO EO=expert opinion. 3: Recommendations for non-pharmacological management of chronic heart failure (CHF) Level of evidence Regular physical activity is recommended.7 All patients with CHF should be referred to an exercise program specifically designed for patients with this condition, if available.7-10 II Patient support by doctor, pre-discharge nurse review with or without home visit is crucial for preventing deterioration in CHF status.11,12 II Sleep apnoea frequently coexists with CHF; patients with obstructive sleep apnoea may benefit from nasal continuous positive airway pressure.13 III CHF patients who have an acute exacerbation or are clinically unstable should have bed rest until their condition improves.14 IV Dietary sodium should be limited to below 200mg daily.15 IV Fluid intake should generally be limited (1.5 litres daily in mild to moderate CHF and 1 litre daily in severe CHF), especially if coexistent with hyponatraemia.16 IV Alcohol intake should generally be nil, but should not exceed 10-20g/day.16 IV Smoking should be strongly discouraged. EO Patients with CHF should be advised to weigh themselves daily and to consult their doctor if their weight increases by more than 1.5kg in a 24-hour period, or if they experience dyspnoea, oedema or abdominal bloating. EO Patients with CHF should be vaccinated against influenza and pneumococcal disease. EO Long flights may predispose to an exacerbation of CHF and should be undertaken with caution. High-altitude destinations should be avoided. Travel to very humid or hot climates should be undertaken with caution and fluid status should be carefully monitored. EO EO=expert opinion. Remaining evidence levels adapted from National Health and Medical Research Council Guideines.17 4: Recommendations for prevention of chronic heart failure (CHF) and treatment of asymptomatic left ventricular (LV) dysfunction Level of evidence All patients with asymptomatic systolic LV dysfunction should be treated with an angiotensin-converting enzyme (ACE) inhibitor and maintained on this therapy indefinitely, unless they are intolerant.18-20 I Antihypertensive therapy should be used to prevent subsequent CHF in patients with elevated blood pressure levels.21-27 I Commencement of therapy with an ACE inhibitor in patients at high risk of ventricular dysfunction (but without current evidence of ventricular impairment) may be considered in individual patients.20 II ß-Blockers should be used early after myocardial infarction (whether or not the patient has systolic ventricular dysfunction).28,29 II Statin therapy should be used as part of a risk factor management strategy to prevent ischaemic events and subsequent CHF in patients who fulfil criteria for commencement of lipid-lowering therapy.30 II Evidence levels adapted from National Health and Medical Research Council Guidelines.17 5: Recommendations for treatment of symptomatic chronic heart failure (CHF) Level of evidence First-line agents Angiotension-converting (ACE) enzyme inhibitors, if tolerated, are mandatory in all patients with systolic heart failure (left ventricular ejection fraction, <40%), whether symptoms are mild, moderate or severe.31-33 Every effort should be made to up-titrate to highest tolerance dose of ACE inhibitors.34 If this is not possible, a lower dose of ACE inhibitor to none at all. Diuretics should be used if necessary to achieve euvolaemia in fluid-overloaded patients. In patients with systolic left ventricular dysfunction, diuretics should never be used as monotherapy, but should always be combined with an ACE inhibitor to maintain euvolaemia. EO β-Blockers are recommended therapy, unless not tolerated or contraindicated, for patients with systolic CHF who remain mildly to moderately symptomatic despite appropriate doses of ACE inhibitors, as well as use of diuretics to optimise fluid status.35-38 I β-Blockers can also be recommended for patients with advanced symptoms of CHF.39 II Spironolactone is recommended for patients who have severe heart failure despite appropriate doses of ACE inhibitors and diuretics.40 II Angiotensin II receptor antagonists may be used as an alternative to ACE inhibitors for patients who are truly ACE-intolerant because of kinin-mediated adverse effects (eg, cough).41 II Second-line agents Digoxin can be considered in patients with advanced CHF for relief of symptoms and to reduce hopitalisation.42,43 It remains valuable therapy in CHF patients with atrial fibrillation. II Hydralazine and isosorbide dinitrate should be reserved for patients who are truly intolerant of ACE inhibitors, or for whom ACE inhibitors are contraindicated and no other therapeutic option exists.44 II EO=expert opinion. Remaining evidence levels adapted from National Health and Medical Research Guideines.17 Box 6 * With rare exceptions, patients with diastolic heart failure present with symptoms and signs of fluid overload, either pulmonary or systemic congestion, or both. † Choice of therapy will vary according to clinical circumstances (eg, thiazide diuretics in elderly patients or those with systolic hypertension; angiotension-converting enzyme [ACE] inhibitors in patients with left ventricular hypertrophy, diabetes or ischaemic heart disease; β-Blockers in patients with agina).

National Heart Foundation of Australia and Cardiac Society of Australia

Editorial Heart Week 2001: "Get active"! A call to action Include physical activity advice in consultations, especially for those at risk of heart disease MJA 2001; 174: 381-382 The focus of the National Heart Foundation Heart Week, the first week of May, is physical activity and heart disease. This is timely given recent evidence that inactivity is a major risk factor for coronary heart disease (CHD), and that the population risk attributable to inactivity appears to be similar to the risk posed by smoking, raised lipid levels or hypertension.1,2The evidence Much of the epidemiological evidence relates to primary prevention and comes from good-quality observational (cohort) studies. The better-designed studies show stronger relationships and a dose-response relationship between inactivity and CHD; the benefits of increasing activity levels accrue particularly for people who have been inactive.1 Evidence from meta-analyses suggests that people who remain sedentary have about twice the risk of CHD of those who participate in regular activity.3 Replication studies in diverse populations since 1990 have reinforced this evidence. There is consistent evidence that women benefit almost as much as men from regular, moderate-intensity physical activity, as do older adults.4,5 It appears that only recent or current physical activity is beneficial, rather than athleticism in earlier life.6 For all age groups, adopting physical activity reduces the risk of CHD deaths, leading to the maxim that "it is never too late to start being active".5,7 Some of this cardiovascular benefit occurs even at levels of physical activity below those required for aerobic (fitness or cardiorespiratory) training, at levels as low as 50% of the maximal predicted heart rates for age.1,8 However, for the general population, more vigorous activity results in additional benefits. There is also evidence that physical activity may prevent ischaemic stroke.9 The mechanism may be through reducing the risk of thrombus formation, or the effects of physical activity may be mediated through reducing blood pressure levels. These protective effects reducing the incidence and mortality from CHD are independent of the influence of physical activity on other cardiovascular risk factors. Nonetheless, there are direct benefits on other risk factors, with moderate activity contributing to lowered blood pressure, increased high density lipoprotein (HDL) cholesterol level, and improvements to the fibrinolytic system.1,8 More sustained physical activity may also help with weight loss. Physical activity has similar benefits for many patients with established coronary artery disease. In those who become active, these benefits include increased fitness, improved oxygen consumption, and decreases in ischaemic responses.8Biological mechanisms: Researchers have begun to explore the biological mechanisms to explain the benefits of physical activity in preventing CHD. There is controlled-trial evidence that sustained vigorous activity can lead to some regression of atherosclerosis.8,10 Exercise may improve coronary endothelial-dependent vasodilatation responses, possibly leading to recruitment of collateral vessels in ischaemic heart disease.11 However, further work is needed to define the exact biological mechanisms. For patients with CHD, there is clinical evidence of increased functional capacity and improved myocardial perfusion after exercise training, and there may even be some benefits for those with uncomplicated heart failure.8 Cardiac rehabilitation: Although the benefits of cardiac rehabilitation are generally accepted,12 these are multifaceted programs, and the individual benefits of the exercise component are difficult to disentangle from the overall program benefit. The key issue here is that, after myocardial infarction, a much higher proportion of patients in Australia need to complete supervised rehabilitation programs than is currently the case. Risk of acute cardiac events: One well-known paradox is the issue of the increased risk of acute cardiac events in unfit sedentary people who embark on vigorous exercise regimens.13 Although the risk of sudden cardiac events is transiently increased (during and for a half hour after strenuous exertion), this acute increment in risk is much reduced for moderate activity. Overall, even among CHD patients, the long term benefits of activity vastly outweigh the short term risks. Furthermore, it has been shown that the overall risk for primary cardiac arrest is much lower among those who are moderately active.14 Thus, among cardiac patients, vigorous activity should be started with caution and in supervised settings, whereas moderate physical activity should be easier to initiate. In conclusion, almost half of Australian adults do not achieve the health goal of moderate participation in physical activity. Recent trends have shown that physical activity levels are declining (as obesity rates are increasing), and that women, those least advantaged and non-English speakers are more likely to be inactive.15 There is a clear mandate to include physical activity advice in consultations, especially for those at risk of heart disease. Brief advice about activity, delivered in the surgery, can positively influence physical activity levels.16 Adherence to structured activity programs is poor, so that constant reinforcement is useful, as well as recommending types of activity which can become part of everyday life. Some patients will be very active, but still develop CHD. However, on balance, increasing activity is a worthwhile investment of medical practitioners' time. For Heartweek 2001, go for a regular walk, and recommend it to almost every patient! Recommendations for physical activity* Recommendations for the general community are that every Australian adult should accumulate half an hour of moderate-intensity activity on most days of the week. Examples of moderate-intensity activities include regular walking at 4km/hour energetic gardening or lawn mowing swimming doubles tennis, and, possibly golf. These are achievable by most people. *Commonwealth Department of Health and Aged Care. National physical activity guidelines for Australians. Canberra: AGPS, 1999. Adrian E Bauman Professor of Public Health and Epidemiology School of Community Medicine University of New South Wales, Sydney, NSW Terry J Campbell Professor of Medicine University of New South Wales (St Vincent's Hospital), Sydney, NSW United States Department of Health and Human Services. The Surgeon General's report on physical activity and health. Washington, DC: US Government Printing Office, 1996. Bauman A. The use of population attributable risk (PAR) in understanding the health benefits of physical activity. Br J Sports Med 1998; 32: 279-280. Berlin JA, Colditz GA. The meta-analysis of physical activity in the prevention of coronary heart disease. Am J Epidemiol 1990; 132: 612-627. Manson J, Hu FB, Rich-Edwards JW, et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N Engl J Med 1999; 341: 650-658. Wannamethee SG, Shaper AG, Walker M. Physical activity and mortality in older men with diagnosed coronary heart disease. Circulation 2000; 102: 1358. Sherman SE, D'Agostino RB, Silbershatz H, Kannel WB. Comparison of past versus recent physical activity in the prevention of premature death and coronary artery disease. Am Heart J 1999; 138: 900-907. Blair SN, Kohl H, Barlow CE, et al. Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. JAMA 1995; 273: 1093-1098. Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circulation 1999; 99: 963-972. Shinton R, Sagar G. Lifelong exercise and stroke. BMJ 1993; 307: 231-234. Hambrecht R, Niebauer J, Marburger C. Various intensities of leisure time physical activity in patients with coronary heart disease: effects on cardiorespiratory fitness and progress of coronary atherosclerotic lesions. J Am Coll Cardiol 1993; 22: 468-477. Hambrecht R, Wolf A, Gielen S, et al. Effect of exercise upon coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342: 454-460. O'Connor GT, Buring JE, Yusuf S, et al. An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 1989; 80: 234-244. Albert CM, Mittleman MA, Chae CU, et al. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med 2000; 343: 1355-1361. Lemaitre RN, Siscovick DS, Raghunathan TE, et al. Leisure-time physical activity and the risk of primary cardiac arrest. Arch Intern Med 1999; 159: 686-690. Armstrong T, Bauman A, Davies J. Physical activity patterns of Australian adults: results of the 1999 National Physical Activity Survey. Canberra: Australian Institute of Health and Welfare, 2000. (AIHW Catalogue No. CVD 10.) Halbert JA, Silagy CA, Finucane PM, et al. Physical activity and cardiovascular risk factors: effect of advice from an exercise specialist in Australian general practice. Med J Aust 2000; 173: 84-87. Make a comment

Adrian E Bauman · Terry J Campbell

Position Statement Non-valvular atrial fibrillation and stroke prevention Graeme J Hankey, on behalf of the National Blood Pressure Advisory Committee of the National Heart Foundation* MJA 2001; 174: 234-239 Abstract - Warfarin versus control - Aspirin versus control - Warfarin versus aspirin - Warfarin combined with aspirin - Warfarin versus other antiplatelet agents - Who to treat and with what? - Who is at high risk of stroke and thromboembolism without treatment? - Who is at high risk of haemorrhage with anticoagulant treatment? - Recommendations for antithrombotic therapy for AF - References - Authors' details - - More articles on Cardiology and cardiac surgery Abstract Atrial fibrillation (AF) affects 5% of people older than 65 years. Among patients with AF, the risk of stroke averages about 5% per year. The risk of stroke increases cumulatively with increasing age, previous transient ischaemic attack or stroke, hypertension, diabetes, impaired left ventricular function and a large left atrium. Management aims to identify and treat the underlying cause, control the ventricular rate, restore and maintain sinus rhythm, and minimise the risk of stroke. Warfarin reduces the risk of stroke by about two-thirds, and aspirin by about one-fifth. The risk of anticoagulant-associated haemorrhage increases with serious concomitant disease, and with poorly controlled hypertension and poorly controlled anticoagulation. All patients with chronic AF should be considered for oral anticoagulant therapy, and the decision based on the balance between the risks of thromboembolism and bleeding. The recommended INR (international normalised ratio) is 2.0-3.0. Treating 1000 "average" AF patients (ie, those with a 5% per year risk of stroke) with warfarin prevents about 30 strokes and causes at least two episodes of major haemorrhage each year. Treating 1000 AF patients with aspirin prevents about 15 strokes each year. Atrial fibrillation (AF) is a common arrhythmia. Its prevalence increases with age, from about 2% in the general population, to 5% in people older than 65 years, and 10% in people older than 75 years1,2 (E4; level-of-evidence codes are described in Box 13). It may occur as a single episode, a series of recurrent episodes ("paroxysmal" AF), or continuously ("permanent" or "chronic" AF). Atrial fibrillation is an important arrhythmia because it may signify underlying heart disease, it may cause symptoms of decreased cardiac output (eg, malaise, effort intolerance) or palpitations, and it is associated with an increased risk of systemic thromboembolism and stroke. This risk of stroke averages about 5% per year among all individuals in AF, which is about 5-6 times greater than for people of the same age who are in sinus rhythm (E32).1,2 The management of AF has four principal objectives: To confirm and document the arrhythmia; To identify and treat the underlying cause; To relieve symptoms of decreased cardiac output by controlling the ventricular rate and restoring and maintaining sinus rhythm; and To reduce the risk of systemic thromboembolism, particularly stroke. All patients, except perhaps the very elderly and infirm, should undergo investigation for underlying causes of AF, including thyroid function tests and echocardiography (E4).4 In haemodynamically stable patients, β-blockade, verapamil or diltiazem can be used to control the heart rate (E4). Recent-onset AF reverts spontaneously within 24 hours in at least half of patients (irrespective of whether or not they are taking digoxin) (E33).5 Patients who have been in AF for more than 48 hours should be considered for anticoagulation therapy and strategies to restore and maintain sinus rhythm. Warfarin should be administered for three weeks before cardioversion is attempted.6 If cardioversion can not be postponed for three weeks, the patient should undergo anticoagulation therapy with intravenous heparin and warfarin,7 and be considered for transoesophageal echocardiography (TOE) (E32). Cardioversion can probably be undertaken safely (with limited risk of stroke) if TOE excludes left atrial and appendage thrombus (and the patient is treated with heparin and warfarin) (E2).8,9 However, if transoesophageal echocardiography identifies left atrial and appendage thrombus, then cardioversion is contraindicated until the patient has been anticoagulated for at least three weeks (E4). The relative merits of cardioversion by electrical shock and medical therapy have been discussed recently.4,10 Direct current cardioversion has never been subjected to a randomised trial, but appears to be the most effective method of restoring sinus rhythm. Its main disadvantage is the need for general anaesthesia. Digoxin and verapamil are ineffective for converting AF to sinus rhythm. Flecainide or sotalol are the preferred medical therapies in younger patients without structural heart disease, and amiodarone in older patients (E2).11 The chances of successful cardioversion are greater if the AF is of recent onset and the left atrial size is normal (E33).12 After successful cardioversion, warfarin therapy should be continued for at least four weeks to prevent clot formation in the "stunned" left atrium (E33).13,14 Antiarrhythmic drug therapy should also be continued to prevent recurrent AF, but this still occurs in 40%-50% of patients after 12 months' follow-up despite drug therapy. If the patient has a low risk of recurrence of AF (eg, "lone" AF) and remains in sinus rhythm for one month after cardioversion, anticoagulation therapy with warfarin can be ceased (E4). In patients at higher risk of recurrence (Box 2), it may be more appropriate to continue warfarin therapy for longer or indefinitely (E4). For patients who are elderly (in whom AF is usually chronic and antiarrhythmic drug therapy may be risky) or have asymptomatic chronic AF, it is often reasonable to avoid attempted cardioversion, accept the AF and aim for adequate ventricular rate control (digoxin combined with β-blockade, verapamil or diltiazem) and long term anticoagulation therapy (E4). The results of clinical trials in patients with asymptomatic AF (of rate control and antithrombotic therapy versus attempted cardioversion and maintenance of sinus rhythm to avoid warfarin) are awaited. Strategies for reducing the risk of stroke and systemic thromboembolism in patients with AF have been studied in several randomised controlled trials over the past decade.15-25 Warfarin versus control Primary prevention Five large randomised controlled primary prevention trials have shown that, in people with chronic non-valvular AF, warfarin reduced the risk of stroke by about two-thirds (68%; 95% CI, 50%-79%; P < 0.001), from about 4.5% to 1.4% per year overall, with little increase in frequency of major bleeding (warfarin, 1.2%; control, 1.0%), or intracranial haemorrhage (warfarin, 0.3% per year; control, 0.1% per year) (E1).15-19,26 This means that warfarin will prevent about 30 strokes per 1000 patient-years of treatment at a cost of at least two serious bleeding episodes per 1000 patients treated for one year. It must be stressed, however, that this acceptable rate of bleeding was achieved in patients who were carefully selected, screened and closely followed; 53%-93% of eligible patients with AF were not included in the trials because of an increased risk of bleeding. Exclusion criteria included old age (> 75 years), serious illness (liver, kidney, brain or malignant disease), alcoholism, fall risk (eg, syncope), forgetfulness, non-steroidal anti-inflammatory drug therapy, and uncontrolled hypertension. Secondary prevention One secondary prevention trial (the European Atrial Fibrillation Trial [EAFT]) showed that, in people with chronic non-valvular AF and symptoms of previous transient ischaemic attack (TIA) or stroke, who have a risk of stroke of 12% per year, warfarin therapy (target INR, 2.5-4.0) reduced the risk of stroke by about two-thirds (66%; 95% CI, 53%-80%), to 4% per year (E2).20 The annual incidence of major bleeding complications was 2.8% in the anticoagulant group and 0.7% in the placebo group. No intracranial bleeds were identified in patients assigned to warfarin. Thus, warfarin prevents about 80 strokes per 1000 patient-years in patients who have had a TIA or stroke and who are in AF, at a cost of at least 20 serious bleeding episodes per 1000 patients treated for one year. The timing of anticoagulation therapy after recent ischaemic stroke depends on the risk of recurrent thromboembolism (Box 2) and the risk of haemorrhagic transformation of the brain infarct (which is higher within the first two weeks and in patients with large brain infarcts and uncontrolled hypertension [E32]27). Common empirical practice is to treat patients with fibrillating acute ischaemic stroke immediately with aspirin (300 mg daily) and then, depending on the above factors, begin warfarin (5 mg daily) between days three and 14 after stroke onset, aiming to achieve an INR of 2.0.28 However, randomised trials comparing aspirin with heparin during the first two weeks of acute ischaemic stroke among patients in AF show no benefit from early anticoagulation, because any net gains from reduction in recurrent ischaemic stroke are offset by the excess hazards of haemorrhagic stroke (E1).29,30 Aspirin versus control Three primary prevention and three secondary prevention trials have shown that, in people with AF, aspirin reduced the incidence of stroke by 22% (95% CI, 2%-38%), from 5.2% (placebo) to 3.7% (aspirin) per year for primary prevention (absolute risk reduction: 1.5% per year), and from 12.9% (placebo) to 10.4% (aspirin) per year for secondary prevention (absolute risk reduction, 2.5% per year) (E1).31Aspirin was not associated with any significant excess of intracranial haemorrhage (aspirin, 0.16%; control, 0.13%) or major extracranial bleeding (aspirin, 0.5%; control, 0.6%) (E1).31 This means that aspirin might prevent about 10 to 20 strokes per 1000 patient-years of treatment, depending on the type of patient treated and their baseline risk of stroke, with little risk of major bleeding. A speculative interpretation of these data is that, in patients with AF, aspirin prevents strokes due to atherothromboembolism, but not cardiogenic embolism. This interpretation is based on the magnitude of the effect (a 20% relative risk reduction), which is very similar to the effect of aspirin in patients with symptomatic atherothromboembolism of the brain, heart and limbs.32 Whether aspirin combined with adjusted-dose warfarin would be safe and more effective (in preventing both atherothrombotic and cardiogenic strokes) than warfarin alone in patients with AF remains unknown.33 Warfarin versus aspirin The relative benefits and risks of warfarin and aspirin have been studied in three trials,15,20,21 all of which showed that warfarin was associated with half the risk of stroke compared with aspirin (47% relative risk reduction; 95% CI, 28%-61%; P < 0.01) (E1).26 Warfarin combined with aspirin For patients with AF who are at high risk of stroke, adding aspirin (325 mg daily) to low-intensity, fixed-dose warfarin, adjusted to an INR of 1.2-1.5, was not as effective in preventing stroke or systemic thromboembolism as standard adjusted-dose warfarin therapy, maintaining an INR of 2.0-3.0 (event rates, 7.9% per year v. 1.9% per year, respectively; P < 0.0001), and there is no difference in the rates of major bleeding (E2).22 Three subsequent trials also suggested that adjusted-dose warfarin (INR, 2.0-3.0) was superior to low-intensity anticoagulant therapy or an aspirin- anticoagulation regimen (E1).23-25 Warfarin versus other antiplatelet agents An Italian study reported that a new antiplatelet agent, indobufen (100-200 mg twice daily), was as effective as adjusted-dose warfarin (INR, 2.0-3.5) in preventing stroke, systemic embolism, myocardial infarction or vascular death in 916 patients with non-valvular AF and recent (within 15 days) TIA or non-disabling ischaemic stroke (E2).34 The 12-month event rates were 10% in the warfarin group and 12% in the indobufen group (P = 0.47). However, the number of patients and outcome events were quite small, follow-up was short, and it is possible that a true difference was not detected. Future studies are planned to evaluate the safety and effectiveness of other, newer antiplatelet agents (such as clopidogrel, oral glycoprotein IIb/IIIa receptor inhibitors, and oral thrombin inhibitors) and combination antiplatelet therapies (such as aspirin-ticlopidine, aspirin-clopidogrel, and aspirin-dipyridamole) as strategies of thromboprophylaxis in AF. Who to treat and with what? Not all patients with AF benefit from thromboprophylactic treatment. The decision to treat depends on the balance between the risk of thromboemboli without treatment and the risks of thromboemboli and haemorrhage with treatment in each patient, as well as the patient's willingness to accept the potential risks, costs, and inconvenience of treatment in order to possibly benefit. The current profile of individual risk of thromboembolism and bleeding complications (see below) remains imprecise and continues to be refined as new data emerge.7 Who is at high risk of stroke and thromboembolism without treatment? The important independent prognostic factors for an increased risk of stroke among individuals with AF are increasing age, a history of previous TIA or stroke, hypertension, diabetes mellitus, and transthoracic echocardiographic evidence of moderate to severe left ventricular systolic dysfunction (E1).7,26,35-37 Echocardiographic evidence of left atrial enlargement (E2) and left atrial spontaneous echo densities ("smoke"), possibly indicative of stasis of blood, are also significant risk factors for stroke36-39 (E33). These risk factors are cumulative: for people younger than 65 years with no risk factors the untreated annual risk of stroke is about 1%, whereas with one or more risk factors it is about 5%; for people aged 65-75 years with no risk factors the annual risk of stroke is about 4%, and with one or more risk factors it is about 6% per year; and for people older than 75 years with no risk factors the risk of stroke is about 3%-4%, whereas with one or more risk factors it is about 8% (see Box 2) (E1).7,26 Who is at high risk of haemorrhage with anticoagulant treatment? The major risk factors for anticoagulant-associated intracranial haemorrhage include fragile intracranial blood vessels (previous symptomatic cerebrovascular disease, computed tomography brain scan evidence of small vessel disease ["leukoaraioisis"]), high blood pressure (poorly controlled hypertension), and excessive anticoagulation (INR, > 3.5) or factors predisposing to it, such as confusion, dementia, inadequate anticoagulant monitoring, alcoholic liver disease, and a tendency to falls (E2).40,41 Increasing age is a risk factor for all of these risk factors, and is thus a potent risk factor for anticoagulant-associated haemorrhage. Among a subgroup of patients in the Stroke Prevention in Atrial Fibrillation (SPAF) II trial (mean age, 80 years), the rate of intracranial haemorrhage was as high as 1.8% per year in those allocated to warfarin therapy (target INR, 2.0-4.5) and 0.8% among those who were assigned to aspirin (E2).21 Although the target INR in this study was higher than currently recommended (INR, 2.0-3.0), these data suggest that the low rate of intracranial haemorrhage documented in the five primary prevention AF trials15-19 may not apply to very elderly individuals (who were not well represented in many of these trials -- the mean age of the patients studied in the AF trials was 69 years, and only about a quarter were older than 75 years). Recommendations for antithrombotic therapy for AF Current practice necessitates individualisation of therapy after an integrated clinical assessment that evaluates thromboembolic risk due to AF, other potential indications for anticoagulant therapy, risk of haemorrhage, and non-medical factors relating to compliance, capacity to have the INR monitored at least monthly, gait instability, risk of other trauma, and patient values and preferences.42,43 Decision analysis can also be useful.44The role of transthoracic echocardiography (TTE), in addition to excluding structural heart disease in all patients who first present with AF, is to further refine stroke risk in the small group of patients with a low risk of stroke according to clinical factors. Although TOE is more sensitive in detecting left atrial thrombus and spontaneous echo contrast, which are markers for increased risk of thromboembolism,36-39 it is more invasive and is usually only required to improve risk stratification among individuals with a relative contraindication to warfarin or in whom TTE is inadequate. The choices of thromboprophylactic agents for atrial fibrillation include warfarin, which is the most effective but also the most risky treatment, and aspirin, which is less effective than warfarin but safer (E1). The combination of aspirin and low dose warfarin is no more effective than aspirin alone (E1).22,23 The most appropriate treatment regimen is one in which patients at high risk of stroke and low risk of haemorrhage are treated with warfarin, and patients at low risk of stroke or high risk of haemorrhage are treated with aspirin. Who not to treat Individuals with AF who are aged less than 60 years and have no evidence of any concurrent heart disease have a very low risk of a thromboembolic event (about 0.6% per year).45 The potential benefits of aspirin in these patients (which may reduce the risk of stroke by 0.12% per year [20% of 0.6%]) may be offset by an equal potential risk of aspirin-associated haemorrhagic stroke of 0.12%.46 Who to treat with aspirin Aspirin is indicated for individuals in AF who are at fairly low absolute risk of stroke, such as those without any of the independent thromboembolic risk factors listed above, or those at risk of an anticoagulant-related haemorrhage which exceeds the risk of stroke (more than 1% per year) (E1). For some people, such as the elderly and those with hypertension, whose risks of stroke and haemorrhage are both high, the treatment decision can be difficult, and may be determined ultimately by the patient's preferences.42,43Patients taking aspirin should be monitored over time and their treatment changed to warfarin if risk factors emerge; this occurs in 10%-15% of patients being treated with aspirin per year.21 Who to treat with warfarin Warfarin is indicated for individuals with chronic AF who are at high absolute risk of stroke (> 4% per year), such as those with any of the independent thromboembolic risk factors listed above, and a lower risk of haemorrhage (E1) (see Box 2). Similarly, anticoagulant therapy should also be considered in patients with paroxysmal AF, again depending on the thromboembolic risk factors (Box 2) as well as the frequency and duration of the paroxysms. Although clinical trial evidence suggests the stroke rate of patients with paroxysmal AF is similar to that of patients with chronic AF,26 the trials did not specifically examine the benefits of antithrombotic therapy in patients with paroxysmal AF. Furthermore, the range of thromboembolic risk in such patients is likely to be extremely wide, from very low for patients who have one short paroxysm once a year to considerably higher for patients who have daily lengthy paroxysms. What is the optimal target INR? The intensity of oral anticoagulant therapy that provides the best balance between the prevention of thromboembolism and the occurrence of bleeding complications appears to be an INR of between 2.0 and 3.0, but may be lower (INR, 1.8 to 2.0) in patients at greater risk of bleeding (eg, the elderly), and may be higher in patients at greater risk of thromboembolism, such as those with prosthetic heart valves [INR, 3.0-4.0]) (E32).47,48It is important to emphasise that, in people in whom anticoagulant therapy is indicated, the risk of stroke increases substantially when the INR falls below 2.0. Patients with an INR of 1.7 have twice the odds of stroke (95% CI, 1.6-2.4 times), and those with an INR of 1.5 have 3.3 times the odds of stroke (95% CI, 2.4-4.6 times) as those with an INR of 2.047 (E32). What if warfarin therapy needs to be ceased? When cessation of warfarin therapy is required because of other (usually surgical) procedures, it is necessary to stratify the invasiveness of the procedure (minimal versus major) and the short-term risk of thromboembolism. Warfarin can be discontinued for five days before a major procedure and continued at a decreased dose for a minor procedure. Therapy should be reinstituted as soon as possible after invasive procedures. Patients at high risk of thromboembolism (eg, severe mitral stenosis, mechanical mitral prosthesis, left ventricular dysfunction) should be admitted to hospital early for intravenous administration of heparin during warfarin cessation. References Lake FR, Cullen KJ, de Klerk NH, et al. Atrial fibrillation and mortality in an elderly population. Aust N Z J Med 1989; 19: 321-326. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-988. National Health and Medical Research Council. A guide to the development, implementation, and evaluation of clinical practice guidelines. Canberra: NHMRC, 1999. Kilborn MJ. Atrial fibrillation. Med J Aust 1999; 170: 498-504. Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. Ann Intern Med 1987; 106: 503-506. Stoddard MF. Risk of thromboembolism in new onset or transient atrial fibrillation. Prog Cardiovasc Dis 1996; 39: 69-80. Laupacis A, Albers G, Dalen J, et al. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 (5 Suppl): 579S-589S. Klein AL, Grimm RA, Black IW, et al. Cardioversion guided by transesophageal echocardiography: The ACUTE Pilot Study. A randomised, controlled trial. Ann Intern Med 1997; 126: 200-209. Bashir M, Grimm RA, Jaber WA, et al. Elderly patients do not have an excessive risk for complications or recurrence following transoesophageal echocardiography-guided cardioversion of atrial arrhythmias: results from the ACUTE registry. J Am Coll Cardiol 2000; 35 (Suppl A): 119A (abstract no. 1097-73). Catherwood E, Fitzpatrick WD, Greenberg ML, et al. Cost-effectiveness of cardioversion and anti-arrhythmic therapy in nonvalvular atrial fibrillation. Ann Intern Med 1999; 130: 625-636. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000; 342: 913-920. Resnekov L. Present status of electroversion in the management of cardiac dysrhythmias. Circulation 1973; 47: 1356-1363. Lown B, Perlroth MG, Kaidbey S, et al. "Cardioversion" of atrial fibrillation: a report on the treatment of 65 episodes in 50 patients. N Engl J Med 1963; 269: 325-331. Manning WJ, Silverman DI, Gordon SPF, et al. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328: 750-755. Petersen P, Boysen G, Godfredsen J, et al. Placebo-controlled randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. Lancet 1988; i: 175-179. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990; 323: 1505-1511. Stroke prevention in atrial fibrillation study: final results. Circulation 1991; 84: 527-539. Connolly SJ, Laupacis A, Gent M, et al, for the CAFA Study Coinvestigators. Canadian atrial fibrillation anticoagulation (CAFA) study. J Am Coll Cardiol 1991; 18: 349-355. Ezekowitz MD, Bridgers SL, James KE, et al, for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) Investigators. Warfarin in the prevention of stroke associated with atrial fibrillation. N Engl J Med 1992; 327: 1406-1412. Secondary prevention in nonrheumatic atrial fibrillation and transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993; 342: 1255-1262. Warfarin versus aspirin for the prevention of thrombo-embolism in atrial fibrillation. Stroke prevention in atrial fibrillation II study. Lancet 1994; 343: 687-691. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high risk patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638. Gullov AL, Koefoed BG, Petersen P, et al. Mini-dose warfarin and aspirin in atrial fibrillation. Second Copenhagen Atrial Fibrillation Aspirin and Anticoagulation Study (AFASAK 2). Arch Intern Med 1998; 158: 1513-1521. Vermeer F, Langenberg M, Hellemons BS, et al. Primary prevention of arterial thrombo-embolism in non-rheumatic atrial fibrillation: results of the PATAF study. Eur Heart J 1998; 19 (Abstract Suppl): 154. Pengo V, Zasso A, Barberi F, et al. Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998; 82: 433-437. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomised controlled trials. Arch Intern Med 1994; 154: 1449-1457. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial haemorrhage. Facts and hypotheses. Stroke 1995; 26: 1471-1477. Gallus AS, Baker RI, Chong BH, et al, on behalf of the Australasian Society of Thrombosis and Haemostasis. Consensus guidelines for warfarin therapy. Recommendations from the Australasian Society of Thrombosis and Haemostasis. Med J Aust 2000; 172: 600-605. Berge E, Abdelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355: 1205-1210. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349: 1569-1581. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999; 131: 492-501. Collaborative overview of randomised trials of anti platelet therapy. I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994; 308: 81-106. Peverill RE. Warfarin or aspirin: both or others? Med J Aust 1999; 171: 321-326. Morocutti C, Amabile G, Fattapposta F, et al, for the SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. Stroke 1997; 28: 1015-1021. Predictors of thromboembolism in atrial fibrillation: clinical features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992; 116: 1-5. Predictors of thromboembolism in atrial fibrillation: echocardiographic features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992; 116: 6-12. Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation. A prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998; 158: 1316-1320. Fatkin D, Feneley M. Stratification of thromboembolic risk of atrial fibrillation by transthoracic echocardiography: the relative role of left atrial appendage function, mitral valve disease, and spontaneous echo contrast. Prog Cardiovasc Dis 1996; 39: 57-68. Jones EF, Calafiore P, McNeil J, et al. Atrial fibrillation with left atrial spontaneous contrast detected by transoesophageal echocardiography is a potent risk factor for stroke. Am J Cardiol 1996; 78: 425-429. Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med 1996; 156: 409-416. A randomised trial of anticoagulants versus aspirin after cerebral ischaemia of presumed arterial origin. The Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) Study Group. Ann Neurol 1997, 42: 857-865. Man-Son-Hing M, Laupacis A, O'Connor A, Wells G. Warfarin for atrial fibrillation: the patient perspective. Arch Intern Med 1996; 156: 1841-1848. Gage BF, Cardinalli AB, Owens DK. Cost-effectiveness of preference-based antithrombotic therapy for patients with nonvalvular atrial fibrillation. Stroke 1998; 29: 1083-1091. Thomson R, Parkin D, Eccles M, et al. Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation. Lancet 2000; 355: 956-962. Kopecky SL, Gersh BJ, McGoon MD. The natural history of lone atrial fibrillation: a population-based study over three decades. N Engl J Med 1987; 317: 669-674. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke. A meta-analysis of randomised controlled trials. JAMA 1998; 280: 1930-1935. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with non-rheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-546. Cannegieter SC, Rosendal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17. Background and evidence basis of recommendations The National Heart Foundation (NHF) Consensus Guidelines for Non-valvular Atrial Fibrillation and Stroke Prevention were written by Clinical Associate Professor Graeme J Hankey on behalf of the National Blood Pressure Advisory Committee of the NHF, which comprises Professor L Wing (chair), Dr A Boyden, Dr A Dart, Dr K Duggan, Clinical Associate Professor G Hankey, Dr M Nelson, Professor I Puddey, Dr M Stowasser, and Dr J Vial. The draft guidelines were circulated for comment to the above members of the committee, who have clinical and research expertise or interests in hypertension, atrial fibrillation, and stroke prevention. Comment was also sought from the Medical Director of the Heart Foundation, Professor Andrew Tonkin. All comments were incorporated into the final document, which was ratified by the Heart Foundation's Cardiovascular Health Advisory Committee. All available evidence from controlled experimental and observational studies was combined with clinical experience to provide recommendations according to the National Health and Medical Research Council Quality of Evidence ratings.3 Authors' details National Heart Foundation of Australia, Melbourne, VIC. Graeme J Hankey, MD, FRACP, Consultant Neurologist and Head of Stroke Unit, Royal Perth Hospital, Perth, WA, and Clinical Associate Professor, Department of Medicine, University of Western Australia. Reprints will not be available from the author. Correspondence: Clinical Associate Professor G J Hankey, Stroke Unit, Royal Perth Hospital, Wellington Street, Perth, WA 6001. gjhankeyATcyllene.uwa.edu.au * L Wing (chair), A Boyden, A Dart, K Duggan, M Nelson, I Puddey, M Stowasser, J Vial 1: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system3 for assessing the level of evidence: E1 Level I Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1 Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2 Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group. E33 Level III-3 Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV Evidence obtained from case-series, either post-test, or pretest and post-test. Back to text 2: Risk stratification and prophylaxis in atrial fibrillation High risk (6%-12% per year risk of stroke) Age >65 years and hypertension or diabetes Previous transient ischaemic attack (TIA) or stroke Valvular heart disease o Heart failure Recent myocardial infarction Impaired left ventricular function on echocardiography Thyroid disease o Left atrial thrombus or left atrial spontaneous echo contrast (TOE done on basis of clinical suspicion) Treatment: Warfarin (target INR 2.0-3.0) if possible and not contraindicated. Moderate risk (2%-5% per year risk of stroke) Age 65 years and hypertension or diabetes Age >65 years and not in high risk group Treatment: Warfarin (target INR 2.0-3.0) or aspirin 75-300mg daily, depending on individual case and echocardiography findings. Low risk (≤1% per year risk of stroke) Age 65 and no hypertension, diabetes, TIA, stroke, or other clinical risk factors Treatment: None, or aspirin 75-300mg daily. Back to text

Graeme J Hankey

Editorial The medical emergency team: no evidence to justify not implementing change Given the lack of evidence on the effect of the MET system, what should we do? MJA 2000; 173: 228-229 Any senior doctor, on quiet reflection, will recall times as a junior doctor when his or her treatment of an acutely unwell patient in hospital was less than ideal, either because of lack of knowledge, inexperience, or inadequate procedural skills. Many of these patients had delayed diagnosis and treatment, but survived in spite of (our) incompetence; others "did not do well". This reality has provided material for popular entertainment, including Doctor in the house,1The house of God,2 and the more recent television medical dramas. In the real world, the challenge of ensuring appropriate and effective treatment of acutely ill hospital patients has been politely ignored. There is a prevailing culture of acceptance that it has always been thus, and is an unfortunate result of the need for the young doctors to gain experience. This "blind eye" attitude is becoming harder to sustain in the face of growing evidence of the magnitude of the problem. The high rate of preventable adverse events in hospitals has been well documented in studies such as the Harvard Medical Practice Study3 and the Quality in Australian Health Care Study.4 Further, studies of inpatients admitted to intensive care units have shown that suboptimal diagnosis and treatment before admission is common.5-7 In the face of this evidence, various efforts to improve the performance of junior medical staff have been made. More consultant involvement, formal training of junior medical staff, greater development of acute care guidelines, and cross-specialty audit and peer review have also been supported.6,8 Those not wishing to change can claim there is no evidence to justify changing... Those who wish to change can claim there is no evidence to justify not changing. A different approach, which amounts to a "re-engineering" of the treatment process for acutely ill inpatients, has been the development of the medical emergency team (MET).9 This has been simply described as a renaming of the cardiac arrest team, together with a widening of calling criteria, so that the team can be called (by the ward nurse) for any patient who is acutely unwell. This is a useful summary description, although the MET system includes a number of other important aspects. These include development of evidence-based criteria for diagnosing the acutely unwell patient, formalised training and inservicing for both the team and the ward nurses, ongoing audit and quality improvement, and institutional supervision. The system has some similarities to the trauma team concept, which became generally introduced a decade ago. Since the introduction of portable defibrillation, comprehensive efforts to improve survival after inhospital cardiac arrest have been disappointing in their effect.10 The appeal of a strategy of early intervention is hard to deny. The concept of the MET system is intuitively appealing to many, and has attracted interest locally (in the National Demonstration Hospital Program)11 and internationally.12,13 But does it work? In this issue of the Journal, Bristow and colleagues attempt to provide an answer.14 In a complex study using innovative statistical methods, they have compared patient outcomes in three hospitals, one of which has had the MET system in place for six years. The study has not clearly demonstrated any difference in death rates associated with the MET system; they conclude there may be a reduction in unplanned admissions to the intensive care unit (ICU). There are a number of methodological shortcomings in this study. Comparison of performance between hospitals is difficult, and casemix adjustment is imperfect at best. Casemix adjustment does not include socioeconomic differences in patient population, funding levels, staffing ratios, medical and nursing staff expertise, and "cultural" differences between hospitals. It is notable that the casemix-adjusted death rate differs markedly between the two non-MET hospitals in the study, presumably because of these and other factors. This difference is of such magnitude that any effect of the MET team (if there is one) is likely to be overwhelmed. The rate of "do not resuscitate" orders appears to be higher in the MET hospital. Admission criteria for ICU may differ between hospitals. The MET team appears to be underutilised in the intervention hospital, while the control hospitals that chose to participate in the study may already emphasise the importance of responding to acutely ill inpatients, reducing the potential benefit of the MET system. Other outcomes could be considered, including the effectiveness of treatment for non-ICU patients, and stress or satisfaction among nursing and medical staff. Many of these shortcomings are unavoidable, and the authors have attempted to address their hypothesis using appropriate methods. They are to be congratulated on this courageous attempt to provide an answer to the difficult issue of the effectiveness of the MET system. This study has produced neither a positive nor a negative result -- it has shown how difficult getting a clear result will be. This is disappointing, but is not surprising given the complexity of the study. Even with the best methodology, it may not be possible to quantify the effect of the MET system. Hospitals are "chaotic" systems, and may be impervious to analysis using linear methodology. In this and other areas, it may be futile to attempt to go beyond qualitative research, despite the lack of traditional respectability of non-quantitative methods. This problem has been powerfully discussed by Runciman,15 among others. Given this lack of "evidence" that the MET system achieves different patient outcomes to the traditional "system" of responding to acutely ill patients, what should be done? Medical traditionalists will advocate no change. The MET system bypasses the traditional medical hierarchy, and it may be claimed that this will "deskill" the junior medical staff. The cost of the MET system is unclear, but ICUs will claim that it increases their workload (although it may reduce ICU admissions). Other objections may relate to the internal politics of hospitals: the MET system empowers nursing staff to involve medical officers other than those nominally working for the admitting medical officer who "owns" the patient. Those not wishing to change can claim there is no evidence to justify changing. In contrast, those who support the MET system will claim that the inevitable delays in the hierarchical system and the lack of skills among junior medical staff make the traditional system inherently inadequate. The MET system is claimed to be an appropriate way to deal with this, intuitively more rational, and a more efficient system for ensuring rapid and appropriate interventions for acutely ill inpatients. Institutional supervision, audit and quality improvement is facilitated. Those who wish to change can claim there is no evidence to justify not changing. The debate is not just between these two extremes. There are important issues still to be resolved, such as the appropriate composition and leadership of the MET, skill and training requirements, and the relative merits of the various specialties that could be involved. The debate includes passionate views about the skills of medical registrars, the importance of keeping management of the patient under the sole control of the admitting team (which is presumed to be omnipresent), and the potential for improving the current system by better emergency protocols and staff training. The situation is very reminiscent of the controversy and debate about the introduction of the trauma team. The deficiencies of existing in-hospital trauma care were recognised for many years,16 but the introduction of trauma teams was debated with many of the same arguments now used about the MET.17 What would the patients -- the general public -- think? Outside of hospitals, an untrained lay person can summon ambulances, paramedics and even helicopters for an acutely ill person. Their calls are monitored and recorded. On the patient's arrival in the emergency department, a structured patient triage system is used to optimise efficiency and outcomes. The performance of this emergency system is audited and analysed. In recent years questions in Parliament, Commissions of Inquiry, and (perhaps) contribution to a change of government have followed reports of inadequate speed or quality of response by out-of-hospital emergency services, and in emergency departments. The contrast with the traditional in-hospital system, based on a university-trained nurse summoning the most junior medical officer as the start of an emergency response, and without systematic institutional supervision, audit, and quality improvement, seems incongruous. The general public, increasingly aware of reports of the inadequacies of hospitals, may be bemused by the persistence of the traditional model of emergency response in hospitals, which is little changed from a century ago. The current unsatisfactory situation requires action. The available evidence does not provide clear direction. The MET system is a rational and reasonable change that may improve patient care, and is unlikely to make things worse. Those who support the traditional model should produce evidence on which to base their resistance to change. In the absence of such evidence, the widespread introduction of the Medical Emergency Team system should proceed. Ross K Kerridge Anaesthetist, John Hunter Hospital Newcastle, and Editorial Chair Australian Resource Centre for Hospital Innovation (www.archi.net.au) mdrkkATcc.newcastle.edu.au Gordon R. Doctor in the house. London: Michael Joseph, 1952. Shem S. The house of God. London: Bodley Head, 1978. Brennan TA, Leape LL, Laird N, et al. Incidence of adverse events and negligence in hospitalised patients: results of the Harvard Medical Practice Study I. N Engl J Med 1991; 324: 370-376. Wilson R McL, Runciman WB, Gibberd RW, et al. The Quality in Australian Health Care Study. Med J Aust 1995; 163: 458-471. McGloin H, Adam S, Singer M. The quality of pre-ICU care influences outcome of patients admitted from the ward. Clin Intensive Care 1997; 8: 104. McQuillan P, Pilkington S, Allan A, et al. Confidential inquiry into quality of care before admission to intensive care. BMJ 1998; 316: 1853-1858. Smith AF, Wood J. Can some in-hospital cardio-respiratory arrests be prevented? A prospective survey. Resuscitation 1998; 37: 133-137. Leah V, Coats TJ. In-hospital resuscitation -- what should we be teaching? Resuscitation 1999; 41: 179-183. Lee A, Bishop G, Hillman KM, Daffurn K. The Medical Emergency Team. Anaesth Intens Care 1995; 23: 183-186. Varon J, Marik PE, Fromm RE. Cardiopulmonary resuscitation: a review for clinicians. Resuscitation 1998; 36: 133-145. Commonwealth Department of Health and Aged Care. A qualitative review of the National Demonstration Hospital Program Phase 2. Canberra: Commonwealth of Australia, 1999. Available at <http://www.health.gov.au:80/hsdd/acc/ndhp/ pubs/ndhp2review.htm>. Garrard C, Young D. Suboptimal care of patients before admission to intensive care. BMJ 1998; 316: 1841-1842. Singer M, Little R. ABC of Intensive Care: Cutting edge. BMJ 1999; 319: 501-504. Bristow PJ, Hillman KM, Chey T, et al. Rates of in-hospital arrests, deaths and intensive care admissions: the effect of a medical emergency team. Med J Aust 2000; 173: 236-240. Runciman WB. Qualitative versus quantitative research -- balancing cost, yield, and feasibility. Anaesth Intens Care 1993; 21: 502-505. Hoffman E. Mortality and morbidity following road accidents. Ann R Coll Surg Engl 1976; 58: 233-240. Spencer JD. Why do our hospitals not make more use of the concept of a trauma team? BMJ 1985; 290: 136-138. Make a comment

Ross K Kerridge

Editorial Alcohol: the good, the bad and the ugly It may be protective against cardiovascular disease, but alcohol is not all good MJA 2000; 173: 231-232 Many recent studies from various countries have consistently highlighted the good effects of alcohol.1 This protective association with alcohol is fairly specific to cardiovascular disease and does not seem to operate for other causes of death. The studies support the notion that the National Health and Medical Research Council (NHMRC) recommendation of two standard drinks a day for women and four standard drinks a day for men2 is sensible advice. That, however, is not the end of the alcohol story. Virtually all of us, as medical students, were exposed to the "bad" of alcohol. Our texts provided lists of diseases caused by the direct effects of high-risk alcohol consumption, as well as the effects of acute intoxication, dependence and withdrawal. Our experience in the wards reinforced these descriptions. In 1997, 3290 Australians (70% men) died of injury and disease caused by high-risk drinking.3 Most of them died of stroke, alcoholic cirrhosis, road injury, suicide, or alcohol dependence. On average, 19 years of life were lost for each person who died of an alcohol-caused condition. At the same time, high-risk drinking was responsible for 72 300 hospitalisations and 403 795 hospital bed-days in Australia; these were predominantly due to falls, alcohol dependence, assaults, or road injuries.3 As medical students, we also witnessed the havoc wrought by alcohol-associated injuries. Between 1990 and 1997, 31% of all driver and pedestrian deaths on Australian roads were alcohol related.4 More than 70% of people with serious alcohol-related road injuries were male (compared with 56% of people with serious non-alcohol-related road injuries). More than half these men were between the ages of 15 and 24 years. The "ugly" was often not seen by medical students. The psychosocial and economic effects of alcohol were rarely spoken about or observed. The annual cost of alcohol misuse in Australia has been estimated at $3.8 billion -- a substantial amount of this is a result of decreased occupational productivity, often a result of hangover-related absenteeism and poor job performance.5 It is estimated that 75% of men and women who have consumed alcohol report that they have experienced hangovers at least once, and 15% experience hangovers at least monthly.5 The leading causes of burden of disease in 15-24-year-old Australian males include alcohol dependence and harmful use, and three other disorders that are related to alcohol: road traffic accidents, suicide, and self-inflicted injury.6 World-wide, alcohol is the fourth leading cause of disability, involving 15.8 million people. In First World regions it is the leading cause, and in Third World regions it is the fourth largest cause, of male disability.7 The recently published National Survey of Mental Health and Wellbeing8 indicates that most Australians (83% of men and 63% of women) report that they have consumed at least 12 drinks of alcohol in the preceding year, and one in 15 (6.5%) have had an alcohol-use disorder in the past 12 months. More men (9.4%) than women (3.7%) had an alcohol-use disorder in the past 12 months, and this is greatest among 18-34-year-olds (almost 16% of men). There is considerable comorbidity between alcohol use and other mental disorders.8 Forty-eight per cent of Australian women with an alcohol-use disorder also suffer from anxiety, affective or other drug-use disorders, compared with 15% of women without alcohol-use disorder; 34% of men with an alcohol-use disorder have another mental disorder. The relation between alcohol and mental disorders is complex: each may cause the other, or both may be related to some underlying cause. Alcohol can also have a devastating effect on families -- more than two-thirds of domestic incidents are alcohol related. Are we making headway against these problems? The initial good news, that since 1978 alcohol consumption in Australia has been progressively falling, is tempered by the slowing of this fall since 1993, and a slight increase in some States. The 1998 National Drug Strategy Household Survey found evidence of increased binge drinking and a softening of attitudes to drinking and driving. In dealing with the problems of alcohol, we need to be aware of two phenomena: Many alcohol-related problems in the community occur in a very large number of people consuming, on a long term basis, above-average but socially acceptable quantities of alcohol, rather than in the much smaller number of persons consuming very large quantities of alcohol.9 Much of the damaging effect of alcohol, particularly in young people, results from episodic (binge) drinking rather than dependent daily consumption of alcohol. These findings have important public health implications. The first point can be partially but effectively addressed by brief intervention strategies delivered by trained GPs as part of their usual strategies.10 However, the second point requires a greater public health commitment to responsible social drinking. Linking alcohol taxes to the alcohol content of beverages is one useful strategy.11 Our strategies need to recognise that people can drink acutely in damaging fashion even if their average weekly consumption is less than the NHMRC limits. Greg Whelan Professor, Department of Drug and Alcohol Studies St Vincent's Hospital, and Physician, Turning Point Alcohol and Drug Centre Inc, Melbourne, VIC Alan T Gijsbers Physician, Department of Drug and Alcohol Studies St Vincent's Hospital, and Turning Point Alcohol and Drug Centre Inc, Melbourne, VIC Doll R. The benefit of alcohol in moderation. Drug Alcohol Rev 1998; 17: 353-363. Pols RG, Hawks DV. Is there a safe level of daily consumption of alcohol for men and women? 2nd ed. Canberra: AGPS, 1992. Chikritzhs T, Jonas H, Heale P, et al. Alcohol caused deaths and hospitalisations in Australia, 1990-1997. National Alcohol Indicators Bulletin No. 1, December 1999. Chikritzhs T, Stockwell T, Heale P, et al. Trends in alcohol-related road injury in Australia, 1990-1997. National Alcohol Indicators Bulletin No. 2, May 2000. Wiese JG, Shiplak MG, Browner WS. The alcohol hangover. Ann Intern Med 2000; 132: 897-902. Mathers C, Vos T, Stevenson C. Burden of disease and injuries in Australia. Canberra: Institute of Health and Welfare, 1999. Murray CJL, Lopez AD. The Global Burden of Disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge, Mass: Harvard University Press on behalf of the World Health Organization and the World Bank, 1996. Teesson M, Hall W, Lynskey M, et al. Alcohol and drug use disorders in Australia: implications of the National Survey of Mental Health and Wellbeing. Aust N Z J Psychiatry 2000; 34: 206-213. Kreitman N. Alcohol consumption and the preventive paradox. Br J Addiction 1986; 81: 353-363. Bien TH, Miller WR, Tonigan JS. Brief interventions for alcohol problems: a review. Addiction 1993; 88: 315-336. Richardson J. Alcohol taxes: the case for reform. Med J Aust 1990: 152: 619-620. Make a comment

Greg Whelan · Alan T Gijsbers