Cardiovascular diseases

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. 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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

Research Rates of in-hospital arrests, deaths and intensive care admissions: the effect of a medical emergency team Peter J Bristow, Ken M Hillman, Tien Chey, Kathy Daffurn, Theresa C Jacques, Sandra L Norman, Gillian F Bishop and E Grant Simmons MJA 2000; 173: 236-240 Abstract - Methods - Results - Discussion - Conclusion - Acknowledgements Authors' details - - More articles on Emergency medicine Abstract Objectives: To evaluate the effectiveness of a medical emergency team (MET) in reducing the rates of selected adverse events. Design: Cohort comparison study after casemix adjustment. Patients and setting: All adult (≥ 14 years) patients admitted to three Australian public hospitals from 8 July to 31 December 1996. Intervention studied: At Hospital 1, a medical emergency team (MET) could be called for abnormal physiological parameters or staff concern. Hospitals 2 and 3 had conventional cardiac arrest teams. Main outcome measures: Casemix-adjusted rates of cardiac arrest, unanticipated admission to intensive care unit (ICU), death, and the subgroup of deaths where there was no pre-existing "do not resuscitate" (DNR) order documented. Results: There were 1510 adverse events identified among 50 942 admissions. The rate of unanticipated ICU admissions was less at the intervention hospital in total (casemix-adjusted odds ratios: Hospital 1, 1.00; Hospital 2, 1.59 [95% CI, 1.24-2.04]; Hospital 3, 1.73 [95% CI, 1.37-2.16]). There was no significant difference in the rates of cardiac arrest or total deaths between the three hospitals. However, one of the hospitals with a conventional cardiac arrest team had a higher death rate among patients without a DNR order. Conclusions: The MET hospital had fewer unanticipated ICU/HDU admissions, with no increase in in-hospital arrest rate or total death rate. The non-DNR deaths were lower compared with one of the other hospitals; however, we did not adjust for DNR practices. We suggest that the MET concept is worthy of further study. Certain in-hospital deaths may be preventable.1-3 Nearly 85% of hospital inpatients who suffer a cardiorespiratory arrest have documented observations of deterioration in the eight hours before the arrest.4,5 Recent studies have demonstrated suboptimal care of hospitalised patients before their admission to the intensive care unit (ICU), and that these patients have a higher mortality.6-8 The authors of these studies urge earlier intervention. One approach to providing an early response to at-risk inpatients throughout the hospital is the medical emergency team (MET),9,10 which replaces the conventional cardiac arrest team. The MET responds to specific clinical criteria (such as bradycardia, tachycardia, hypotension and threatened airway) in order to prevent further deterioration. Others have advocated similar approaches to reduce unexpected hospital deaths and morbidity.11,12 In our study, selected outcomes in a hospital with a MET were compared with outcomes in two hospitals with conventional cardiac arrest teams. These outcomes were rates of cardiorespiratory arrest, unanticipated admission to the ICU or high dependency unit (HDU), death, and deaths where there was no prexisting "do not resuscitate" (DNR) order. Methods This study was a prospective cohort comparison of three hospitals, testing whether an early intervention team, the MET, was associated with fewer adverse events among inpatients, after adjusting for casemix differences. The study was approved by the ethics committees of each participating hospital and the University of New South Wales. Setting The hospitals were similarly sized Australian public hospitals, with bed capacities in the range 380-530. At Hospital 1, the cardiac arrest team was replaced by a MET, which any staff member could call for immediate assistance. Staff could summon the MET if concerned about a patient's condition or if the patient's vital signs exceeded certain levels (Box 1).10 An education program explained the MET's role to all new staff. However, calling the MET when criteria were met was not compulsory. The MET consisted of the ICU registrar and senior nurse, and medical registrar. At Hospitals 2 and 3, the arrest team was paged by nursing or medical staff for cardiorespiratory arrest. The arrest team consisted of the ICU registrar, medical registrar, and ICU or coronary care nurse. Data collection We identified all cardiorespiratory arrest calls, deaths, and ICU/HDU admissions at the three hospitals among patients 14 years and over in hospital during the period from 8 July to 31 December 1996. These were designated "events". Soon after an event, the patient's medical record was reviewed for demographic information. In addition, for cardiac arrests and deaths, documentation of a DNR order before arrest or death was recorded. Each ICU/HDU admission was classified as to whether the patient was admitted to ICU/HDU for the same reason he or she was admitted to hospital. If not, the ICU/HDU admission was defined as unanticipated. For example, a patient admitted to ICU with respiratory distress after a cholecystectomy would be unanticipated. Data were collected by three critical care nurses (one at each hospital) trained in the use of a specifically designed form, which was piloted for two weeks before data collection. The nurses were familiar with the medical record at the three hospitals. Where the information contained in the history was unclear, the attending staff were asked for clarification. Data were entered into a database.13 Data cleaning was performed and any anomalies checked by reference to the datasheet or medical record. Data were then exported to SAS14 for analysis. Outcome measures The primary endpoints were the casemix-adjusted rates of ICU/HDU unanticipated admission, cardiac arrest, death, and deaths without a prior DNR order. These were called "total event rates". For any patient, one event could result in additional events (eg, cardiac arrest followed by unanticipated ICU admission and then death). The "index event" was defined as the event the data collectors considered the first in a series of events. The casemix-adjusted rates of index events were compared between the three hospitals as secondary endpoints. To ensure that any decline in the rate of unanticipated admissions was not caused by excess anticipated admissions, the casemix-adjusted rate of all ICU/HDU admissions was calculated as a control measure. Casemix adjustment Demographic and diagnostic data on the patient population (aged ≥ 14 years) admitted to the hospitals for the period were obtained. The study data were merged by medical record number and date of admission with the complete inpatient statistical data to create a dataset with 50 942 records. This enabled us to identify the admissions for which an event occurred and analyse the data at the patient level. Using simple and multiple logistic regression, we modelled the probability of an event occurring during hospitalisation, adjusted for patient demographics and diagnostic characteristics. Models were derived independently for each total event and for each index event. Parameters were added to the model in a stepwise fashion. To prevent overparameterising the models (where minor, non-significant differences cumulatively hide true differences), when C (equivalent to the area under the receiver operator characteristics curve) reached 0.85 no further parameters were added to the model. This always occurred with fewer than six parameters used. Demographic and casemix independent variables that were tested for use in the models are detailed in Box 2. The models developed used groups of diagnostic categories based on ICD-9-CM codes using the principal diagnosis and the stay diagnosis only.15 The ICD-9-CM code groupings used are available from the principal author (PJB). The performance of the models was assessed by Hosmer-Lemeshow goodness-of-fit tests.16 The risk of an event occurring in a hospital compared with the MET hospital was presented as an adjusted odds ratio with 95% confidence intervals. A level of significance of 5% was used in all statistical tests. Results Hospital demographics Characteristics of all patients (aged ≥ 14 years) admitted to the three hospitals during the study period are shown in Box 3. Hospital 2 had fewer admissions than the other hospitals. Hospital 1 had a higher proportion of male patients admitted, and a lower proportion of admissions from the emergency department (ED). This hospital also had a younger patient population, which is reflected in differences in casemix: Hospital 1 had lower proportions of patients with stroke, severe acute heart disease, gastrointestinal disease, and musculoskeletal and connective tissue diseases, but higher proportions with severe trauma and follow-up care without acute diagnosis (eg, dialysis). The rates of DNR orders in dying patients were 77% in Hospital 1, and 64% and 70% in Hospitals 2 and 3, respectively (P = 0.006). Prevalence and characteristics of events A total of 1510 adverse events (unanticipated ICU/HDU admissions, arrest calls, and deaths) were recorded during the study period for the three hospitals. There were 1100 index events. The prevalence and characteristics of events are summarised in Box 4 for total event rates and Box 5 for index rates. There was a significantly reduced rate of unanticipated ICU/HDU admissions at the MET intervention hospital after casemix adjustment (for both the total event rate and the index rate). After adjustment, Hospital 2 had 49 (95% CI, 20-87) more unanticipated ICU/HDU admissions over a six-month period, and Hospital 3 had 92 (95% CI, 47-146) more, compared with Hospital 1. The rate of all ICU/HDU admissions was lower at Hospital 1 than at one control hospital, and trended to lower than at the other. There was no statistically significant difference in cardiac arrest rate or death rate after casemix adjustment. The casemix-adjusted death rate in patients where there was no documentation found of a DNR order was significantly higher at Hospital 2, translating to 27 (95% CI, 7-53) extra non-DNR deaths. Model performance Box 6 presents an example of the odds ratios after addition of the most significant variables in the multiple logistic regression models derived from the data for the total arrest data. It shows the C statistic as each variable was added to the cardiac arrest model. In the cardiac arrest models, the variables that were adjusted for were emergency admissions, age over 74, heart disease, lung disease and infectious disease as diagnoses. In the total death models, the terms adjusted for were emergency admissions, age over 74, single day stay emergency admissions, and cancer and infectious disease. The same demographic variables were used in the index death model, although in the total non-DNR death model both age ≥ 75 and age 65-74 were used in the model. In the unanticipated ICU/HDU models, the variables adjusted for were single day admission, emergency admission, and cancer and gastrointestinal disease diagnoses. The total unanticipated ICU/HDU model also included the variables stroke and infectious disease as diagnoses. All models satisfied the Hosmer- Lemeshow test.16 Discussion Rationale for our methods In this study, we attempted to determine if the MET system was associated with a reduced rate of adverse events among inpatients. To do this, we compared the rates of adverse events between three hospitals after casemix adjustment.17-19 This method was chosen as we decided that randomisation at the patient level was impractical. A random pattern of response to calls would probably have dissuaded staff caring for patients from calling the MET. Randomisation by ward would have risked contamination bias and engendered problems of casemix, as wards differ in the nature of their patients. Historical comparison at Hospital 1 between a period before and a period after introduction of the MET team was impractical, as the team had been trialled and evolved for six years before the study. The models we used appear to adequately fit the data, according to the Hosmer-Lemeshow goodness-of-fit tests, and with good model performance measured by C statistics. However, multiple methods of casemix adjustment are possible, and these may give divergent results. This is a limitation of casemix adjustment methodology.20 To avoid concealing real differences by excessive modelling, parameters were added stepwise by multivariate analysis until the models reasonably represented the data. The terms which appeared in the final models were usually those that could be expected to influence the outcomes. Thus, advanced age and emergency admissions were factors in the death and cardiac arrest models. The cardiac arrest models also included the terms for heart disease, lung and infectious disease. Infectious disease was an unexpected variable and was also significant in the total death model. Other differences (such as levels of hospital funding, ICU/HDU capacity, the number and seniority of medical and nursing staff, and the level of out-of-hours cover) may also have contributed to the results. However, to adjust for these would have been more difficult than for the variables studied, which relate directly to the patients at risk and are easily and reliably obtained. Explanation of findings After casemix adjustment, we found reduced rates of both total and index unanticipated ICU/HDU admissions at the MET intervention hospital. There were no differences in the rates of cardiac arrests or deaths. However, at one hospital without the MET, there was a higher rate of non-DNR deaths, the subset of deaths most likely potentially preventable by a MET. The reduction in unanticipated ICU/HDU admissions that was seen in the MET intervention hospital could result from many factors. One possible explanation is that the MET was effective and able to intervene on the wards and prevent further deterioration. Another possible reason may relate to differences in referral practices: perhaps the presence of MET backup engendered a feeling that ICU/HDU referral was not needed. Misclassification of ICU/HDU admissions as anticipated rather than unanticipated was excluded as an explanation of the difference by the finding that the rate of all ICU/HDU admissions was lower at the intervention hospital than one control hospital and trended to lower at the other. The lack of efficacy of the MET to prevent cardiorespiratory arrest and modify death rate may be related to lack of sensitivity of calling criteria, or because pathophysiological processes (eg, shock) become irreversible. Another possible explanation for the lack of effect of the MET on event rates is underutilisation. Based on a previous study,21 up to 706 MET calls could have been expected, and yet only 150 were made. Frequent education is probably also required to ensure the appropriate calling of a MET.22 No special efforts regarding staff education in the study period were made. The clinical staff of the hospital were unaware of the study, to negate any possible Hawthorne effect.23 Finally, organisational changes such as introduction of a MET are difficult to implement in hospitals.24,25 Our results probably reflect the effectiveness of the implementation of the MET system as much as the concept of early intervention. Future directions Our study cannot answer definitively if the MET was the cause of the benefit we observed; it does show that the MET concept is worthy of further study. The study could be likened to a Phase II trial of a drug comparing three hospitals at one point in time. Further studies of the MET system's efficacy are needed, such as a before-after comparison in several hospitals, or a comparison of a larger sample size of intervention and control hospitals. Such studies should be repeated some time after the intervention. Is the benefit observed useful and worth pursuing? If it is possible to reduce unanticipated ICU admissions without increased mortality this may result in cost saving. It has been estimated that the US spends about 1% of its gross national product on intensive care facilities.26 However, any savings in intensive care would be offset by the cost of establishing and maintaining a MET. The MET may also have unexpected costs and benefits on processes such as staff satisfaction with care provided. Again, these need to be quantified. Conclusion In this study, we found that fewer patients were unexpectedly admitted to ICU or HDU at a hospital with the MET system, and this hospital had fewer non-DNR deaths than one of the other hospitals. There was no significant change in the casemix-adjusted rate of arrests or total deaths. This may be an advantage of an early response team, which could have important implications for patient care in hospitals. We believe that the MET concept should be studied further in a larger sample of institutions. Acknowledgements Funding for the study was provided by a Commonwealth Department of Health and Family Services Research and Development Grant (HS338). Associate Professor Robert Gibberd assisted with the statistical analysis. References 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. Leape LL, Brennan TA, Laird N, et al. Nature of adverse events in hospitalised patients: results of the Harvard Medical Practice Study II. N Engl J Med 1991; 324: 377-384. Wilson R McL, Runciman WB, Gibberd RW, et al. The Quality in Australian Health Care Study. Med J Aust 1995; 163: 458-471. Schein RMH, Hazday N, Pena M, et al. Clinical antecedents to inhospital cardiopulmonary arrest. Chest 1990; 98: 1388-1392. Franklin C, Mathew J. Developing strategies to prevent inhospital cardiac arrest: analyzing responses of physicians and nurses in the hours before the event. Crit Care Med 1994; 22: 246-247. Lundberg JS, Perl TM, Wiblen T, et al. Septic shock: an analysis of outcomes for patients with onset on hospital wards versus intensive care units. Crit Care Med 1998; 26: 1020-1024. Goldhill DR, Sumner A. Outcome of intensive care patients in a group of British intensive care units. Crit Care Med 1998; 26: 1337-1345. McQuillan P, Pilkington S, Allan A, et al. Confidential inquiry into quality of care before admission to intensive care. BMJ 1998; 316: 1853-1858. Lee A, Bishop G, Hillman KM, Daffurn K. The medical emergency team. Anaesth Intensive Care 1995; 23: 183-186. Hourihan F, Bishop G, Hillman KM, et al. The medical emergency team: a new strategy to identify and intervene in high risk patients. Clin Intensive Care 1995; 6: 269-272. Frank ED. A shock team in a general hospital. Anesth Analg 1967; 46: 740-745. Goldhill DR. Introducing the postoperative care team [editorial]. BMJ 1997; 314: 389. Microsoft Access [computer program]. Version 2.0. Redmond, Wa: Microsoft, 1994. SAS for Windows [computer program]. Version 6.12. Cary, NC: SAS Institute Inc, 1997. Stremple JF, Bross DS, Davis CL, McDonald GO. Comparison of postoperative mortality and morbidity in VA and nonfederal hospitals. J Surg Res 1994; 56: 405-416. Hosmer DW, Lemeshow S. Applied logistic regression. New York: John Wiley and Sons, 1989. Iezzoni LI. The risks of risk adjustment. JAMA 1997; 278: 1600-1607. Dubois RW, Rogers WH, Moxley JH, et al. Hospital inpatient mortality. Is it a predictor of quality? N Engl J Med 1987; 317: 1674-1680. Green J, Passman LJ, Wintfield N. Analyzing hospital mortality. The consequences of diversity in patient mix. JAMA 1991; 265: 1849-1853. Iezzoni LI, Shwartz M, Ash A, et al. Severity measurement methods and judging hospital death rates for pneumonia. Med Care 1996; 34: 11-28. Hillman KM, Bishop G, Lee A, et al. Identifying the general ward patient at high risk of cardiac arrest. Clin Int Care 1996; 7: 242-243. Daffurn KD, Lee A, Hillman KM, et al. Do nurses know when to summon emergency assistance? Intensive Crit Care Nurs 1994; 10: 115-120. Grufferman S. Complexity and the Hawthorne effect in community trials [editorial]. Epidemiology 1999; 10: 209-210. Garside P. Organisational context for quality: lessons from the fields of organisational development and change management. Qual Health Care 1998; 7 Suppl: S8-15. Koeck C. Time for organisational development in healthcare organisations [editorial]. BMJ 1998; 317: 1267-1268. Cerra FB. Healthcare reform: the role of coordinated critical care. Crit Care Med 1993; 21: 457-464. (Received 15 Feb, accepted 10 Jul, 2000) Authors' details Liverpool Hospital, Sydney, NSW. Peter J Bristow, MB BS, FRACP, Staff Specialist, Department of Intensive Care; Ken M Hillman, MB BS, FFICANZCA, Professor, University of New South Wales Clinical School; Kathy Daffurn, RN, MAppSc, Co-Director, Division of Critical Care; Sandra L Norman, MN, BAppSc, Clinical Nurse Specialist, Department of Intensive Care; Gillian F Bishop, MB ChB, FFICANZCA, Director, Department of Intensive Care; Tien Chey, BSc, MAppStat, Statistician, Epidemiology Unit. Department of Intensive Care, St George Hospital, Sydney, NSW. Theresa C Jacques, MB BS, FFICANZCA, Director. Department of Intensive Care, Illawarra Regional Hospital, Wollongong, NSW. E Grant Simmons, MB BS, FFICANZCA, Director. Reprints will not be available from the authors. Correspondence: Dr P J Bristow, Intensive Care Offices, Alfred Hospital, Commercial Road, Prahran, VIC 3181. p.bristowATalfred.org.au Make a comment 1: Criteria for calling the medical emergency team10 Cardiorespiratory arrest Threatened airway Respiratory rate ≤5 breaths per minute ≥36 breaths per minute Pulse rate ≤40 beats per minute ≥140 beats per minute Systolic blood pressure ≤90mmHg Repeated or prolonged seizures Fall in Glasgow Coma Score >2 points Concern about patient status not detailed above Back to text 2: Variables available for calculation of the various models Sex (binary) Seven age categories (14-24, 25-34, 35-44, 45-54, 55-64, 65-74, ≥75) Same-day admission (binary) (ie, admission and discharge occurred on the same calendar day) Referral from emergency department (binary) Australian born (binary) Casemix categories (16 indicator variables, available from author) Hospital (three indicator variables) Back to text 3: Characteristics of admissions at the three study hospitals from 8 July to 31 December 1996 Hospital* Characteristic 1 2 3 Test of Independence† Number of admissions 18338 13059 19545 Male admissions 44.9% 42.9% 42.8% χ2=21.06‡ (2 df) Same-day admissions 47.7% 47.0% 46.7% χ2=4.35 (2 df) Admission via emergency department 29.6% 36.0% 35.1% χ2=186.53‡ (2 df) Australian born Country of birth not stated 49.3% 6.8% 67.2% 0.5% 50.2% 23.2% Not tested Age distribution 14-24 25-34 35-44 45-54 55-64 65-74 ≥75 9.7% 14.9% 14.3% 12.4% 18.1% 20.5% 10.0% 8.6% 15.2% 9.6% 9.8% 18.5% 22.2% 16.0% 7.8% 13.1% 11.1% 10.4% 14.4% 22.1% 21.1% χ2=1146‡ (12 df) Diagnostic category 1. Cancer 2. Stroke 3. Severe acute heart disease 4. Metabolic and electrolyte disorders 5. Pulmonary disease 6. Ophthalmologic disease 7. Low risk heart disease 8. Gastrointestinal disease 9. Urologic disease 10. Musculoskeletal, connective tissue disease 11. Infectious diseases 12. Symptoms and ill-defined conditions 13. Severe trauma 14. Follow-up care without acute diagnosis 15. Pregnancy, childbirth, puerperium 16. Others 4.4% 1.4% 2.6% 1.3% 3.3% 2.0% 3.5% 6.4% 1.9% 1.8% 1.0% 3.2% 2.9% 34.0% 10.8% 19.5% 4.1% 1.8% 3.0% 1.6% 2.9% 1.2% 2.9% 8.9% 1.7% 3.4% 0.7% 3.0% 2.1% 30.1% 14.1% 18.5% 5.3% 1.6% 3.2% 1.1% 4.2% 0.5% 4.6% 10.2% 1.9% 3.2% 1.0% 6.7% 1.8% 23.4% 11.0% 20.5% χ2=1562‡ (50 df) *Hospital 1 had the medical emergency team. †Test for any difference between the three hospitals. ‡P Back to text 4: Comparisons of total event rates by hospitals Event n Crude rates/10000 Unadjusted ORs Adjusted ORs* Cardiac arrest Hospital 1 Hospital 2 Hospital 3 69 66 99 38 51 51 1.00 1.34 (0.96-1.89) 1.35 (0.99-1.83) 1.00 1.14 (0.81-1.61) 1.00 (0.73-1.37) Death Hospital 1 Hospital 2 Hospital 3 243 240 295 133 184 151 1.00 1.39 (1.16-1.67) 1.14 (0.96-1.35) 1.00 1.08 (0.89-1.30) 0.83 (0.70-1.00) Non-DNR death Hospital 1 Hospital 2 Hospital 3 55 86 88 30 66 45 1.00 2.20 (1.57-3.09) 1.50 (1.07-2.11) 1.00 1.68 (1.19-2.36) 0.94 (0.67-1.33) Unanticipated ICU/HDU admission Hospital 1 Hospital 2 Hospital 3 118 146 234 64 112 120 1.00 1.73 (1.36-2.21) 1.86 (1.49-2.32) 1.00 1.59 (1.24-2.04) 1.73 (1.37-2.16) *Odds ratios (ORs) adjusted for patient characteristics and diagnostic categories. Hospital 1 (which has the medical emergency team) is the reference for the ORs. For shaded ORs, 95% CIs do not cross 1.0. DNR="do not resuscitate" order documented. ICU=intensive care unit. HDU=high dependency unit. Back to text 5: Comparisons of index event rates by hospitals Event n Crude rates/10000 Unadjusted ORs Adjusted ORs* Cardiac arrest Hospital 1 Hospital 2 Hospital 3 60 63 84 33 48 43 1.00 1.48 (1.04-2.10) 1.31 (0.94-1.83) 1.00 1.24 (0.87-1.78) 0.96 (0.69-1.35) Death Hospital 1 Hospital 2 Hospital 3 119 139 191 65 106 98 1.00 1.65 (1.29-2.11) 1.51 (1.20-1.90) 1.00 1.24 (0.97-1.60) 1.05 (0.82-1.33) Unanticipated ICU/HDU admission Hospital 1 Hospital 2 Hospital 3 82 140 222 45 107 114 1.00 2.41 (1.83-3.17) 2.56 (1.98-3.30) 1.00 2.17 (1.65-2.87) 2.35 (1.82-3.04) *Odds ratios (ORs) adjusted for patient characteristics and diagnostic categories. Hospital 1 (which has the medical emergency team) is the reference for the ORs. For shaded ORs, 95% CIs do not cross 1.0. ICU=intensive care unit. HDU=high dependency unit. Back to text 6: An example of how the odds ratios and C statistic changed as variables were added stepwise to the model for total cardiac arrests Odds ratio* (95% CI) Hospital 2 Hospital 3 C statistic Crude odds ratio Admission via emergency department Age ≥75 years Severe acute heart disease Low risk heart disease Infectious disease Pulmonary disease 1.34 (0.96-1.89) 1.16 (0.83-1.63) 1.06 (0.75-1.49) 1.06 (0.75-1.49) 1.07 (0.76-1.50) 1.09 (0.77-1.53) 1.14 (0.81-1.61) 1.35 (0.99-1.83) 1.19 (0.87-1.62) 0.98 (0.72-1.34) 0.99 (0.72-1.35) 0.99 (0.72-1.35) 1.00 (0.73-1.37) 1.00 (0.73-1.37) 0.533 0.755 0.798 0.809 0.826 0.833 0.850 *Hospital 1 is the reference for the odds ratios. Back to text

Peter J Bristow · Ken M Hillman · Tien Chey · Kathy Daffurn · Theresa C Jacques · Sandra L Norman · Gillian F Bishop

Editorial Alcohol and cardiovascular disease: still a research priority? MJA 2000; 173: 116-117 More precision in measuring drinking levels and patterns will give a firmer basis for advice about drinking The evidence amassed to date on the link between moderate alcohol intake and reduced risk of dying of cardiovascular disease might be thought already sufficient to bracket sceptics of alcohol's protective effect with doubters of manned lunar missions and members of the Flat Earth Society. Published studies demonstrating this link can now be counted in the hundreds, and no fewer than six plausible underlying biological mechanisms have been identified.1 In this issue of the Journal yet another study reports this link: Simons and colleagues show moderate alcohol intake to be associated with increased survival in elderly people.2 Their study is an elegant example of the genre and drawn from a highly respected prospective study of risk factors for death and illness in the population of Dubbo, New South Wales. The two fields of epidemiology and alcohol studies have much to learn from each other Alternative explanations for the protective effect of moderate alcohol intake, relying on ever more tenuous confounding effects, have been discredited one by one. The apparently protective effect of moderate alcohol consumption has so far survived the use of controls for sociodemographic status,3 for the "sick quitter hypothesis"4 (ie, the suggestion that many abstainers have stopped drinking because of serious illness), for the amount of cholesterol in the diet,5 and even for the degree of social isolation.6 As evidenced in the study by Simons et al,2 the protective effect is fairly specific to cardiovascular disease and does not operate for other major causes of death in older people such as cancer. While a handful of recent studies have failed to find a protective effect for moderate drinking,7,8 these are still heavily outnumbered by those with positive findings.1 In fact, the range of different countries and cultures in which the phenomenon has been documented is also testimony to its robustness, even if different levels of consumption appear to provide the benefit in different drinking cultures.1 So, does medical science need further research on this topic? My contention is that, while the basic protective properties of moderate alcohol consumption appear to have been identified, the precision of the measurement of drinking levels and patterns in these studies needs to be sharpened if we are to have a firmer basis for advising people how to drink to avoid ill-health. The recent major systematic review commissioned by the National Health and Medical Research Council to underpin revisions to Australia's national guidelines on low risk drinking found that nearly all epidemiological studies in this area only attempt to measure one of the important dimensions of alcohol consumption: total volume of drinking, usually expressed as average intake per day.1 Despite recent evidence that pattern of drinking plays a role independent of volume,9 large-scale epidemiological studies rarely include simple items in their questionnaires tapping this dimension, such as frequency of drinking five or more drinks in one day, or maximum amount consumed on one day. Simons et al make a rare contribution to our knowledge by providing an analysis of mortality risk, based not only on average volume of alcohol across all days, but also on usual amount consumed on a drinking day. Clearly, these can be very different measures (eg, seven drinks in a day once a week versus one drink every day of the week).2 While the power of the analyses in Simons et al is limited by sample size, usual consumption of five or more drinks for men and of three or four drinks in a day for women was not associated with a significantly reduced risk of death.2 It should be noted, however, that questions regarding "usual" consumption tend to suffer from a bias towards low-consumption occasions and against less frequent occasions of high intake.10 Forthcoming World Health Organization guidelines on measurement of alcohol consumption advise that a superior method is the "graduated quantity frequency", in which respondents are asked how often they drink at each of different levels of consumption, starting with the highest (eg, "How often do you drink 20 drinks on one day?").10 The same guidelines identify another problem bedevilling attempts to convert the results of alcohol studies into precise advice for drinkers: assumptions about the alcohol content of drinks reported vary between studies and are usually not empirically based. A number of studies from different countries have attempted to document usual-serve sizes employed by random samples of drinkers and found these to vary significantly from those usually assumed by researchers.11,12 One study found that the bias created towards under-reporting of consumption was massive in one particular population subgroup: Afro-American women.13 One striking consequence of a failure to measure pattern of alcohol consumption adequately can be the false identification of special benefits from one type of alcoholic beverage over another. Wine is often reported as being most associated with benefits, but being a wine drinker as opposed to a beer and spirits drinker is a marker for many other things, including a tendency towards a more consistent pattern of daily drinking rather than occasional "bingeing".14 A well known Danish study,3 often cited as evidence for a greater benefit of wine over other drinks, measured alcohol consumption by only asking about how much people usually drank if they drank every day. Because this is a less frequent pattern for heavy drinkers of beer and spirits, many of the latter will have been falsely categorised as light or moderate drinkers, thus significantly biasing against finding protective effects for these beverages. The two fields of epidemiology and alcohol studies have much to learn from each other. If epidemiological studies of risk factors for heart disease do not improve their measurement of patterns and levels of alcohol use, it will remain very hard to give precise advice to drinkers who wish to minimise harms and maximise benefits of alcohol consumption. In reality, despite hundreds of studies into the protective effects of alcohol in relation to heart disease, research into this area has only just begun. Timothy R Stockwell Director National Centre for Research into the Prevention of Drug Abuse Curtin University of Technology, Perth, WA Single E, Ashley MJ, Bondy S, et al. Evidence regarding the level of alcohol consumption considered to be low-risk for men and women. Final report. Canberra: National Health and Medical Research Council, 2000. URL: <http://www.nhmrc.health.gov.au/advice/alc-comp.htm> (accessed 29 June 2000). Simons LA, McCallumJ, Friedlander Y, et al. Moderate alcohol intake is associated with survival in the elderly: the Dubbo Study. Med J Aust 2000; 173: 121-124. Gronbaek M, Deis A, Sorensen TIA, et al. Mortality associated with moderate intakes of wine, beer or spirits. BMJ 1995; 310: 1165-1169. Rehm J, Sempos CT. Alcohol consumption and all-cause mortality: questions about causality, confounding and methodology. Addiction 1995; 90: 493-498. Rehm J, Sempos CT. Alcohol consumption and all-cause mortality. Addiction 1995; 90: 471-480. Murray RP, Rehm J, Shaten J, Connett JE. Does social integration confound the relation between alcohol consumption and mortality in the Multiple Risk Factor Intervention Trial (MRFIT)? J Stud Alcohol 1999; 60: 740-745. Leino EV, Romelsjo A, Shoemaker C, et al. Alcohol consumption and mortality. II. Studies of male populations. Addiction 1998; 93: 205-218. Hart CL, Smith GD, Hole DJ, Hawthorne VM. Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: results from a prospective cohort study of Scottish men with 21 years follow up. BMJ 1999; 318: 1725-1729. Rehm J, Ashley KJ, Room R, et al. On the emerging paradigm of drinking patterns and their social and health consequences. Addiction 1996; 91: 1615-1621. World Health Organization (Substance Abuse Department). International guidelines for monitoring alcohol consumption and harm. Geneva: WHO. In press. Stockwell T. Information provided in Australia about the size of "standard drinks". Med J Aust 1992; 156, 295. Lemmens P. The alcohol content of self-report "standard drinks". Addiction 1994; 89: 593-602. Kaskutas L, Graves K. An alternative to standard drinks as a measure of alcohol consumption. Paper presented at International Conference on the Measurement of Drinking Patterns, Alcohol Problems and the Connection; 2000 April 2-7; University of Stockholm, Sweden. In press. Doll R. One for the heart. BMJ 1997; 315: 1664-1668. Make a comment

Timothy R Stockwell

Research Moderate alcohol intake is associated with survival in the elderly: the Dubbo Study Leon A Simons, John McCallum, Yechiel Friedlander, Michael Ortiz and Judith Simons MJA 2000; 173: 121-124 For editorial comment, see Stockwell Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Cardiology and cardiac surgery Abstract Objective: To examine the relationship between alcohol intake and survival in elderly people. Design and setting: A prospective study over 116 months of non-institutionalised subjects living in Dubbo, a rural town (population, 34 000) in New South Wales. Participants: 1235 men and 1570 women aged 60 years and over who were first examined in 1988-89. Main outcome measures: All-causes mortality; gross cost of alcohol per life-year gained. Results: Death occurred in 450 men and 392 women. Intake of alcohol was generally moderate (ie, less than 14 drinks/week). Any intake of alcohol was associated with reduced mortality in men up to 75 years and in women over 64 years. In a proportional hazards model, the hazard ratio for mortality in men taking any alcohol was 0.63 (95% CI, 0.47-0.84) and in women was 0.75 (95% CI, 0.60-0.94). Cardiovascular deaths in men were reduced from 20/100 (95% CI, 14-26) to 11/100 (95% CI, 9-13) and in women from 16/100 (95% CI, 13-19) to 8/100 (95% CI, 6-10). The reduction in mortality occurred in men and women taking only 1-7 drinks/week -- hazard ratios, 0.68 (95% CI, 0.49-0.94) and 0.78 (95% CI, 0.61-0.99), respectively, with a similar protective effect from intake of beer or other forms of alcohol. After almost 10 years' follow-up, men taking any alcohol lived on average 7.6 months longer, and women on average 2.7 months longer, compared with non-drinkers. The gross cost for alcohol per life-year gained if consuming 1-7 drinks/week was $5700 in men, and $19 000 in women. Conclusions: Moderate alcohol intake in the elderly appears to be associated with significantly longer survival in men 60-74 years and in all elderly women. The consumption of moderate amounts of alcohol, compared with abstention or with heavy alcohol intake, appears to be associated with reduced all-causes mortality in middle-aged subjects.1-3 This effect may be partially mediated through a reduced risk of coronary heart disease (CHD)4 and stroke.5 Some studies attribute the protection to a specific effect of wine;6,7 other studies attribute it to any type of alcohol.8In elderly people, some of this benefit from moderate alcohol intake may be negated by mortality from other causes.9 In a prospective study of men and women aged 65 years and over in the United States (Established Populations for Epidemiologic Studies of the Elderly), alcohol intake under 21 drinks/week was associated with a 30%-40% lower all-causes mortality in two cohorts, but with no influence in a third cohort.10 In Australian men and women aged 60 years and over with 77 months' follow-up, the intake of 1-7 drinks/week was associated with a 22%-25% reduction in all-causes mortality, although this reduction did not achieve statistical significance.11 We have examined the relationship between alcohol intake and survival in this Australian cohort during a more extended follow-up of 116 months. We present the results and include an economic analysis of moderate alcohol intake. Methods Dubbo Study The Dubbo Study is an ongoing prospective examination of cardiovascular and other diseases in an elderly Australian cohort first examined in 1988-89. All non-institutionalised residents of Dubbo, New South Wales, born before 1930 were eligible; participation rate was 73% (1235 men and 1570 women). Methods and measures have already been described in detail.12,13 The baseline examinations comprised demographic, psychosocial and standard cardiovascular risk assessments, including examination of fasting blood samples. Alcohol usage Questions on alcohol usage were those asked in the National Heart Foundation Risk Factor Prevalence Study,14 and yielded an approximation of usual alcohol intake coded as zero, 1-7, 8-14, 15-28 and more than 28 drinks/week (referring to a standard drink containing 10 g of alcohol). Specific intakes of beer, wine and spirits were not separately sought, but subjects were asked whether they normally drank beer or not, allowing a separation of drinking behaviour into beer and "other". Survival analysis Outcomes from August 1988 to 31 December 1998 were included in the analysis, a median 116 months' follow-up. Hospitalisation and death records were monitored continuously, and postal surveys were conducted every two years to confirm vital status. The survey in 1997 successfully traced more than 98% of surviving participants. Records were coded according to the International classification of diseases, ninth revision, clinical modification (ICD-9-CM). The independent contribution of any risk factor to mortality was examined in a Cox proportional hazards model. Point estimates and 95% CIs for the relative hazard of death were calculated from the regression coefficients (presented as hazard ratio, a measure of relative risk). The models included categories of alcohol intake as described above, and, where relevant, a categorical term describing whether a subject normally drank beer or "other" (ie, wine/spirits). The proportional hazards model assumes constant relative hazard over the length of follow-up. This assumption was confirmed for each model by a plot of log-minus-log survival, demonstrating parallel curves over all categories of alcohol intake. Statistical analyses were conducted using SPSS for Windows NT.15 Economic analysis A weighted alcohol acquisition cost per week using the midpoint of the intake ranges was calculated for each alcohol intake stratum and for each sex using 1999 Dubbo club prices. Individuals were assumed to remain in their initial consumption strata over the whole time period. Survival curve data from the Cox model were used to calculate total expenditure on alcohol, as well as survival benefit for each stratum of intake. An incremental analysis (difference in cost/difference in benefit) was conducted using the no-alcohol-consumption stratum as the reference. This yielded an estimate of the gross cost per life-year gained. Although the study collects hospitalisation records, hospitalisation costs were not available and a net cost per life-year gained could not be estimated. Ethical approval The study was approved by the institutional ethics committees at St Vincent's Hospital, Sydney, the University of New South Wales and the Australian National University. All participants gave informed, written consent. Results Pattern of alcohol intake The pattern of alcohol intake and its clinical associations have been fully documented in an earlier report.11 The pattern of alcohol intake, by quantity and type, is shown in Box 1. On a day when alcohol was consumed, 40% of all men and 45% of all women took one or two drinks, 23% and 7% took three or four drinks, and 15% and 1%, respectively, took five or more drinks. All-causes mortality Death occurred in 450 men (36%) and 392 women (25%). Consumption of more than 14 drinks/week was uncommon. Hence, where relevant, the use of alcohol has been grouped into zero use and any use. Alcohol intake: Age-specific all-causes mortality by alcohol intake is presented in Box 2. Alcohol use in men appeared to be associated with reduced mortality up to age 74 years, but not beyond. In women, its use was associated with reduced mortality in all groups older than 64 years. Predictors of all-causes mortality: The independent contribution of alcohol to all-causes mortality was explored in men 60-74 years and in all women in proportional hazards models which adjusted for the presence of major demographic, psychosocial and cardiovascular variables at study entry. The significant predictors of all-causes mortality are summarised in Box 3. (Alcohol intake was not a significant predictor of mortality in men aged more than 74 years.) Any alcohol intake was significantly associated with reduced all-causes mortality in both sexes. Quantity or type of alcohol intake: The relationship between quantity or type of alcohol intake and all-causes mortality in the proportional hazards model is presented in Box 3. The risk of mortality was significantly reduced at all levels of alcohol intake, except in women taking 15-28 drinks/week (representing only 3% of women in the study). A similar degree of reduction in all-causes mortality was observed at all levels of alcohol intake. The protection observed was broadly similar in those using beer versus wine/spirits, although this only reached statistical significance for beer consumption. Pattern of alcohol intake: In a subsequent model, the quantity of alcohol consumed per week was replaced by a variable denoting the usual number of drinks taken on a given day, a measure of the pattern of drinking. Using zero intake as the reference group, the hazard ratio in men with a consumption of one or two drinks on a given day was 0.64 (95% CI, 0.46-0.89), with three or four drinks 0.68 (95% CI, 0.47-0.98), and with five or more drinks 0.69 (95% CI, 0.45-1.06). The corresponding hazard ratios in women were 0.74 (95% CI, 0.59-0.93), 0.68 (95% CI, 0.38-1.22) and 1.38 (95% CI, 0.58-3.29) (there were only 17 women in this group). Hazard curves: The hazard curves calculated from the proportional hazards models in men and women are presented in Box 4. By the end of almost 10 years' follow-up, men taking any alcohol lived on average 7.6 months longer, and women on average 2.7 months longer, than their counterparts taking no alcohol. Specific causes of death: Cardiovascular death (ie, CHD and stroke) was reduced from 20/100 (95% CI, 14-26) in non-drinkers to 11/100 (95% CI, 9-13) in men taking any alcohol. The corresponding reduction in cardiovascular death in women was from 16/100 (95% CI, 13-19) to 8/100 (95% CI, 6-10). Deaths attributed to any cancer were unchanged in men (6/100 [95% CI, 3-9] versus 7/100 [95% CI, 5-9]) and in women (4/100 [95% CI, 2-6] versus 5/100 [95% CI, 3-7]). Gross cost for alcohol per life-year gained From the number of life-years added to survival for each quantity of intake, we have estimated the gross cost for alcohol per life-year gained. In men 60-74 years and in women 60 years and over taking 1-28 drinks/week, the respective costs were $13 000 and $31 000 per life-year gained. Since much of the benefit from alcohol intake was observed at a moderate intake of only 1-7 drinks/week, the respective costs at this intake were $5700 and $19 000 per life-year gained. Discussion In this well-defined, community-based sample of rural elderly Australians, alcohol intake could be described as moderate rather than heavy.11 Our results confirm that any intake of alcohol is associated with significantly reduced all-causes mortality in men 60-74 years and in all elderly women, consistent with our previous report at 77 months' follow-up.11 Statistical significance has now been reached due to the greater number of deaths and increased statistical power. Absolute death rates in men were substantially higher than in women, especially in the "young old". This would account for the greater average survival advantage shown in Box 4 (7.6 months versus 2.7 months). Equivalent reductions in mortality occurred at 1-7 drinks/week and at higher intakes. In men there was no evidence of a differential effect between 1-2 drinks on a given day and an intake of five or more drinks on a given day. Not all studies have documented an association between all-causes mortality and alcohol intake.16,17 The reduction in CHD and stroke mortality associated with alcohol use we observed is consistent with findings of previous reports,8,18,19 as well as those of recent reports in large middle-aged cohorts from the United States.4,5,20 These data are gradually causing health authorities to reconsider public policy on moderate alcohol intake, say 1-7 drinks/week, in the prevention of future morbidity and mortality.21 Studies in younger populations indicate a "U"- or "J"-shaped relationship between alcohol intake and all-causes mortality.2 This has not been a general finding in the elderly, possibly because these cohorts contain an excess of "healthy survivors".10 It is surprising that we could find no relationship between alcohol intake and mortality in men aged over 74 years, but it is plausible that very elderly men lose the benefit of alcohol intake because they become subject to competing causes of mortality.9 There is a potential for misclassification of alcohol intake between zero and low intake because of under-reporting. This would diminish any apparent relative benefit of alcohol intake on all-causes mortality. Hence, our statistically significant findings may represent a minimum estimate of the benefit of moderate alcohol intake. We have demonstrated essentially a "threshold effect" between alcohol intake and all-causes mortality in either sex. Protection does not improve greatly as alcohol intake increases further (Box 3). Thus, under-reporting would then have less impact on our findings. This threshold effect is important, particularly if we were to move to a public health position of suggesting that abstainers should begin to imbibe! The economic findings take no account of any changes in healthcare costs arising downstream through the benefits or otherwise of alcohol intake. What we regard as an acceptable cost per life-year gained is arbitrary, but it is informative to compare our calculated costs with, for example, recently published gross costs for the use of simvastatin in patients with established CHD, with survival increased by around 20%.22 Assuming such patients receive lifetime therapy with simvastatin from their mid-50s, the gross cost per life-year gained in the UK population would be £5100 (or about $13 000). Although one is comparing unrelated "therapy", moderate alcohol intake, at least in older men, may turn out to be a popular and cost-effective means of improving survival which does not require government subsidy! The relative merits of wine versus other forms of alcohol consumption remain controversial. Data from France6 and Denmark7 highlight specific benefits of wine, and this has generated a new research effort to identify which components of wine, apart from alcohol, may be the most beneficial. Antioxidants are among the most prominent suggestions.23 Others consider that alcohol in any form gives protection against cardiovascular disease,8 largely through its effect in raising high density lipoprotein (HDL) cholesterol levels.11 In Dubbo, the quantity of alcohol intake was highly correlated with HDL cholesterol (r = 0.32, P < 0.001 and r = 0.23, P < 0.001 in men and women, respectively). Other suggested mechanisms for cardiovascular protection include favourable effects of alcohol on thrombotic and fibrinolytic pathways, reduced insulin resistance and improved endothelial function through increased nitric oxide production.5 Alcohol may also influence survival in ways which currently defy measurement: regular alcohol intake may reflect a special lifestyle integrated with less tangible factors.21 Although excess alcohol intake is undoubtedly toxic to the central nervous system, recent studies suggest that a moderate intake may reduce the risk of dementia. In a study of elderly French people 65 years and over, appropriately from Bordeaux, the rate of hospitalisation for dementia in non-drinkers over three years was 4.9/100, but only 3.9/100 in those taking any alcohol (with a more striking effect on the risk of Alzheimer's disease).24 During 116 months' follow-up in the Dubbo population, the respective rates of hospitalisation for dementia were 4.3/100 and 2.5/100 (P < 0.01). It is premature to promote the use of alcohol for prevention of dementia, but the 21st century may witness a completely new role for alcohol in health. Acknowledgements The Dubbo Study is supported in part by grants from the National Health and Medical Research Council of Australia, Astra Pharmaceuticals Pty Ltd, Amrad Pharmaceuticals Pty Ltd, Bristol-Myers Squibb Australia Pty Ltd, Merck Sharp & Dohme Australia Pty Ltd, Parke Davis Pty Ltd and Pfizer Pty Ltd. We acknowledge the dedication of the Dubbo Nurse-Manager Kerrie Pearson, the assistance of Gina Brinsmead in economic analysis and Helen Adams in preparation of the manuscript. References Klatsky AL, Armstrong MA, Friedman DD. Alcohol and mortality. Ann Intern Med 1992; 117: 646-654. Holman CDJ, English DR, Milne E, Winter MG. Meta-analysis of alcohol and all-cause mortality: a validation of NHMRC recommendations. Med J Aust 1996; 164: 141-145. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 1997; 337: 1705-1714. Albert CM, Manson JE, Cook NR, et al. Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation 1999; 100: 944-950. Berger K, Ajani UA, Kase CS, et al. Light-to-moderate alcohol consumption and the risk of stroke among US male physicians. N Engl J Med 1999; 341: 1557-1564. Renaud S, Geuguen R, Siest G, Salamon R. Wine, beer, and mortality in middle-aged men from Eastern France. Arch Intern Med 1999; 159: 1865-1870. Gronbaek M, Deis A, Sorensen TIA, et al. Mortality associated with moderate intakes of wine, beer or spirits. BMJ 1995; 310: 1165-1169. Rimm EB, Klatsky A, Grobbee D, Stampfer MJ. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine or spirits? BMJ 1996; 312: 731-735. Van de Water HA, Boshuizen HC. The impact of substitute morbidity and mortality on public health policies. Leiden: TNO Prevention and Health, Division of Public Health and Prevention, 1995. Scherr PA, LaCroix AZ, Wallace RB, et al. Light to moderate alcohol consumption and mortality in the elderly. J Am Geriatr Soc 1992; 40: 651-657. Simons LA, Friedlander Y, McCallum J, Simons J. Alcohol intake and survival in the elderly: a 77 month follow-up in the Dubbo Study. Aust N Z J Med 1996; 26: 662-670. Simons LA, McCallum J, Friedlander Y, et al. Dubbo Study of the elderly: sociological and cardiovascular risk factors at entry. Aust N Z J Med 1991; 21: 701-709. Simons LA, McCallum J, Friedlander Y, Simons J. Predictors of mortality in the prospective Dubbo Study of Australian elderly. Aust N Z J Med 1996; 26: 40-48. Risk Factor Prevalence Study Management Committee. Risk Factor Prevalence Study: Survey No 3 1989. Canberra: National Heart Foundation Australia and Australian Institute of Health, 1990. SPSS for Windows NT [computer program], version 9.0. Chicago, Ill: SPSS Inc, 1999. Leino EV, Romelsjo A, Shoemaker C, et al. Alcohol consumption and mortality. II. Studies of male populations. Addiction 1998; 93: 205-218. Hart CL, Smith GD, Hole DJ, Hawthorne VM. Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: results from a prospective cohort study of Scottish men with 21 years follow up. BMJ 1999; 318: 1725-1729. Hennekens CH, Willett W, Rosner B, et al. Effects of beer, wine and liquor in coronary deaths. JAMA 1979; 242: 1973-1974. Stampfer MJ, Colditz GA, Willett WC, et al. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 1988; 319: 267-273. Sacco RL, Elkind M, Boden-Albala B, et al. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999; 281: 53-60. Hommel M, Jaillard A. Alcohol for stroke prevention? N Engl J Med 1999; 341: 1605-1606. Pickin DM, McCabe CJ, Ramsay LE, et al. Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of treatment. Heart 1999; 82: 325-332. Frankel EN, Kanner J, Germann JB, et al. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993; 341: 454-457. Orgogozo J-M, Dartigues J-F, Lafont S, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris) 1997; 153: 185-192. (Received 23 Dec 1999, accepted 10 Apr 2000) Authors' details University of New South Wales Lipid Research Department, St Vincent's Hospital, Sydney, NSW. Leon A Simons, MD, FRACP, Associate Professor of Medicine; Judith Simons, MACS, Analyst-Programmer. Faculty of Health, University of Western Sydney MacArthur, Sydney, NSW. John McCallum, DPhil, Professor and Dean. Department of Social Medicine, Hebrew University - Hadassah Hospital, Jerusalem, Israel. Yechiel Friedlander, PhD, Associate Professor in Epidemiology. Pfizer Pty Ltd, Sydney, NSW. Michael Ortiz, PhD, Health Outcomes Manager. Reprints will not be available from the authors. Correspondence: Professor L A Simons, Lipid Research Department, St Vincent's Hospital, Darlinghurst, NSW 2010. l.simonsATnotes.med.unsw.edu.au Make a comment Back to text 2: Age-specific all-causes mortality rate and alcohol intake during 116 months' follow-up of subjects 60 years and over. Data are mortality rates per 100 subjects (95% CI and number of subjects in each group in parentheses) Men Women Zero alcohol Any alcohol Zero alcohol Any alcohol 60-64 y 65-69 y 70-74 y 75-79 y 80+ y All ages 26 (17-35) (88) 37 (24-50) (54) 57 (45-69) (65) 51 (35-67) (37) 83 (68-98) (23) 44 (38-50) (267) 17 (13-21) (326) 26 (21-31) (266) 41 (34-48) (184) 64 (55-73)(120) 83 (74-92) (63) 34 (31-37) (959) 9 (5-13) (193) 22 (16-28) (172) 31 (24-38) (154) 45 (36-54) (121) 72 (63-81) (104) 31 (28-34) (744) 10 (7-13) (288) 14 (9-19) (191) 11 (6-16) (166) 36 (27-45) (107) 54 (42-66) (68) 20 (17-23) (820) Back to text 3: Proportional hazards model of all-causes mortality and alcohol intake in elderly subjects Hazard ratio (95% CI) Men 60-74 years Women 60+ years Significant predictors of all-causes mortality Any alcohol intake Age (/year) Current smoker Ex-smoker Prior stroke Blood pressure medication Diabetes Atrial fibrillation Poor expiratory flow 0.63 (0.47-0.84) 1.07 (1.04-1.11) 2.81 (1.90-4.16) 1.76 (1.26-2.46) 1.58 (1.03-2.42) 1.54 (1.16-2.06) 1.99 (1.38-2.87) -- 1.53 (1.09-2.17) 0.75 (0.60-0.94) 1.08 (1.06-1.10) 1.74 (1.22-2.49) -- -- -- 2.06 (1.46-2.92) 2.77 (1.65-4.64) 2.00 (1.43-2.79) Relationship of quantity or type of alcohol to all-causes mortality Drinks/week Nil 1-7 8-14 15-28 >28 1.00 0.68 (0.49-0.94) 0.58 (0.39-0.85) 0.62 (0.40-0.95) 0.56 (0.33-0.96) 1.00 0.78(0.61-0.99) 0.66 (0.45-0.97) 0.67 (0.29-1.55) Alcohol type Nil Beer Wine/spirits 1.00 0.62 (0.46-0.84) 0.70 (0.44-1.12) 1.00 0.64 (0.47-0.86) 0.85 (0.66-1.11) The reference category for alcohol usage was zero intake. Other variables in the models were body mass index, family history of coronary heart disease (CHD), prevalent CHD, blood pressure, lipid levels, self-rated health, and physical disability. Poor expiratory flow refers to peak expiratory flow tertile I. Back to text Back to text

Leon A Simons · John McCallum · Yechiel Friedlander · Michael Ortiz · Judith Simons

Fitness And Health Physical activity and cardiovascular risk factors: effect of advice from an exercise specialist in Australian general practice Julie A Halbert, Christopher A Silagy, Paul M Finucane, Robert T Withers and Phil A Hamdorf MJA 2000; 173: 84-87 Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on General practice and primary care Abstract Objective: To determine whether provision of individualised physical activity advice by an exercise specialist in general practice is effective in modifying physical activity and cardiovascular risk factors in older adults. Design: Randomised controlled trial of individualised physical activity advice, reinforced at three and six months (intervention) versus no advice (control). Setting: Two general practices in Adelaide, South Australia, 1996. Participants: 299 adults aged 60 years or more who were healthy, sedentary and living in the community. Main outcome measures: Changes to physical activity (frequency and duration of walking and vigorous exercise), selected cardiovascular risk factors (blood pressure, body weight, serum lipid levels) and quality of life over 12 months. Results: Self-reported physical activity increased over the 12 months in both groups (P < 0.001). The increase was greater for the intervention than the control group for all measures except time spent walking (P < 0.05). More intervention than control participants increased their intention to exercise (P < 0.001). Serum levels of total and low-density lipoprotein cholesterol and triglycerides fell significantly over the 12 months to a similar extent in the two groups. No other significant changes in cardiovascular risk factors were seen. Quality-of-life scores decreased over the 12 months. The decrease was significantly greater among intervention than control women, but not men, for emotional well-being (P = 0.02), physical well-being (P = 0.04) and social functioning (P = 0.04). Discussion: Provision of general practice-based physical activity advice reinforced three-monthly produced a sustained increase in self-reported physical activity. However, there were no associated changes in clinical measures of cardiovascular risk factors and minimal changes in quality-of-life measures. A large body of evidence shows that all-cause mortality and death and disability from cardiovascular disease decrease with regular physical activity1 and physical fitness.2 Leisure-time activity also reduces coronary risk factors,3 and the greatest decrease is achieved by moving individuals from the sedentary, low-fitness category.4,5Among Australians aged over 60 years, 55% of men and 61% of women are not sufficiently active to maintain general health.6 Encouragingly, a Western Australian survey found that 93% of general practitioners (GPs) reported asking about physical activity when a patient presented with a condition that might benefit from exercise, and 50% asked new patients about current physical activity patterns.7 However, GPs comment on a lack of skill in assessing and guiding activity and a lack of guidelines.8 Although many believe referral to a qualified fitness professional is desirable, fewer than 15% make these referrals.9 Previous studies of interventions to increase provision of advice and patients' physical activity in primary care have had mixed results and are of varying methodological quality.10 To reduce the demand on GPs, several groups have examined the effectiveness of advice from practice staff. Results of advice from a health visitor were initially favourable but were not sustained,11 while advice from practice nurses produced no increases in objectively measured12 or self-reported13 exercise levels in the short term. Therefore, we designed a properly powered study to determine the effectiveness of individualised advice from an exercise specialist in a general practice setting on changing physical activity levels and cardiovascular risk factors at 12-month follow-up. Methods The study was a randomised, controlled trial. Ethics approval was granted by the Committee on Clinical Investigation, Flinders Medical Centre, Adelaide. Recruitment and baseline measures Sedentary adults aged 60 years or over who lived in the community were recruited from two general practices in the southern region of Adelaide, South Australia, in 1996, as described previously.14 Briefly, 2878 people who met the above criteria were invited to a screening appointment; 913 attended and completed a questionnaire on demographic characteristics, medical history, medication use and physical activity levels. Exclusion criteria included a cerebrovascular or ischaemic cardiac event in the previous six months, malignancy or other life-threatening disease, inability to comply with the requirements of the study, a condition for which physical activity was contraindicated, use of β-blocker medication, and regular physical activity, leaving 351 people eligible. These 351 were invited to attend a baseline appointment at which they signed a consent form and were randomly allocated to the intervention or control groups using sealed opaque envelopes. They also answered a written questionnaire about current physical activity levels, intention-to-exercise,15 quality of life (assessed by the Short Form 3616) and demographic information. Blood pressure, body weight and height were measured, and a blood sample was taken for lipid studies. Interventions Both groups had a 20-minute session with an exercise specialist (with a master's degree in exercise physiology; J A H). Spouses were invited to attend these and follow-up sessions, which were held at the participants' usual GP surgeries. The intervention group received individualised advice about the benefits of physical activity and a pamphlet containing a plan for physical activity for the next three months. This plan, based on current position statements,17,18 involved aerobic activities at moderate intensity for a minimum of three sessions per week for at least 20 minutes per session, with self-monitoring of heart rate. The exercise plan, potential barriers to exercise and strategies to overcome these were discussed. The focus was on incorporating physical activity into the individual's usual activities and on increasing "self-efficacy" (belief in one's ability to perform the activity) by recommending a preferred, familiar activity and setting modest targets for the first three months. These targets were to be progressively increased, depending on progress, enthusiasm and health. The control group received a pamphlet promoting good nutrition for older adults, which was discussed for 20 minutes. Follow-up At three and six months, all participants were mailed a follow-up questionnaire to be returned in a postage paid envelope (control participants) or at an interview (intervention participants). This interview was arranged by telephone, and intervention participants were encouraged to attend whatever their adherence to the exercise plan. Participants were also asked to complete a seven-day physical activity log as a prompt for discussion, which included physical activity levels and benefits, reasons for success or failure, injuries, heart-rate monitoring and changes to the plan. At 12 months, all participants were invited to a follow-up interview, at which they completed a questionnaire, and clinical characteristics (except height) were remeasured. Energy expenditure was measured for 59 participants (31 intervention and 28 control participants) over four days (two weekends and two weekdays) using a Caltrac portable, vertical accelerometer.19 These 59 were recruited by telephoning randomly selected participants until six volunteers per week were obtained (a total of 88 were telephoned). Statistical analyses Sample size calculations indicated that 212 people were required to detect a 5 mm Hg difference in systolic blood pressure between the intervention and control group using a parallel group design (assuming a power of 0.9 and type I error rate of 0.05). Targeting 300 subjects allowed for a 40% dropout and non-compliance rate. Assumptions for parametric analysis were investigated. Repeated-measures analyses of variance were used to examine data for physical activity and five quality-of-life scores, using time as the within-subject variable, and time, intervention and sex as the between-subject variables. As data for three quality-of-life scales (roles physical and emotional and social functioning) were non-continuous and skewed, they were dichotomised (score of 100 = 0, score < 100 = 1) and then analysed with generalised estimating equations -- an extension of generalised linear models -- to examine time, intervention and sex interactions.20 Twelve-month changes in clinical characteristics, quality-of-life and accelerometer results were analysed with Student's t tests (independent samples). Intention-to-exercise data were analysed with χ2 statistics. All data were analysed on an intention-to-treat basis. In the event of missing responses, data were entered at the previous follow-up, thereby assuming no change. Results Participants Of the 351 people eligible for the study, 299 attended the baseline interview and were randomised (149 to the intervention group and 150 to the control group). Their characteristics have been reported previously.14 There were no statistically significant differences between the intervention and control groups in age (mean age, 67.3 years [SD, 7.9 years] versus 67.8 years [SD, 5.5 years]), sex distribution (48% versus 44% men), current and past medical history and current medication use or clinical parameters at baseline (Box 1). Three- and six-month follow-up questionnaires were returned by 274 (92%) and 269 (90%) participants, respectively, while 264 (88%) attended the 12-month follow-up interview (123 in the intervention and 141 in the control group). Of the 35 who did not attend, two had died, six were on holidays, seven were ill, and 20 were not interested. There were no statistically significant differences in baseline clinical and sociodemographic measures between participants who attended the 12-month follow-up interview and those who did not. Physical activity At all three follow-ups, all self-reported measures of physical activity had increased significantly from baseline levels in both the intervention and control groups (P < 0.05; Box 2). However, the intervention group reported significantly more physical activity than the control group for all measures except time spent walking (P < 0.05). Men reported significantly more minutes of walking per session (P = 0.02) and more frequent vigorous exercise (P = 0.02) than women at all follow-ups. In addition, the difference in frequency of vigorous exercise between the intervention and control groups was significantly greater for men than for women (P < 0.001). Energy expenditure data were available for 59 participants who wore an accelerometer (31 intervention and 28 control participants). The intervention and control groups did not differ significantly in any measured parameter of energy expenditure -- total per day, per day as a percentage of total energy expenditure, during activity per day, or during activity per kg body weight. At all follow-ups, there were significant differences between the intervention and control groups for change in intention to exercise (P < 0.001). At 12-month follow-up, more intervention than control participants increased their intention to exercise (Box 3). Cardiovascular risk factors Over the 12 months, there were no statistically significant changes in body weight, resting heart rate, blood pressure or serum high-density lipoprotein levels in either the control or intervention group (Box 1). However, there were significant decreases in serum levels of total and low-density lipoprotein cholesterol and triglycerides in both groups; the decreases did not differ significantly between the two. In addition, body weight decreased for all men and for control-group women, but increased for intervention-group women (P = 0.01). Quality of life Quality-of-life scores decreased between baseline and 12-month follow-up in both the intervention and control groups. These score decreases were significant in both groups for bodily pain (P = 0.001), general health (P < 0.001), physical functioning (P < 0.001), vitality (P = 0.04) and role physical (odds ratio [OR], 1.80; 95% CI, 1.33-2.43). Women in the intervention group had significantly greater score decreases than women in the control group for the scales role emotional (P = 0.02), role physical (P = 0.04) and social functioning (P = 0.04). In addition, women reported worse scores at 12-month follow-up than men for bodily pain (P = 0.02), mental health (P = 0.03), physical functioning (P = 0.04) and vitality (P = 0.01), and were 1.5 times more likely to report some difficulty with role physical (OR, 1.43; 95% CI, 1.03-1.99) and social functioning (OR 1.53; 95% CI, 1.06-2.21). Discussion This randomised controlled trial showed that provision of physical activity advice by an exercise specialist was effective in increasing the intention to exercise and self-reported physical activity among patients 60 years and over in two general practices. Other studies have also found increased intention to exercise14 and increased physical activity levels12,21 as a consequence of physical activity advice. However, our study differs from most others in that it had a large number of participants and high retention rate (88% at 12 months), and calculated results on an intention-to-treat basis. The high retention rate possibly resulted from participants' strong association with their GPs, who were aware and possibly encouraging of their participation, and the fact that all visits were conducted at the GPs' practices. The success of the intervention may be attributed to the enthusiastic volunteer population, who, while sedentary, were keen to start regular activity. Another possible contributor was the strong emphasis on walking as the preferred activity. The physical activity advice had the characteristics of successful physical activity interventions -- a home-based program, comprising unsupervised, informal exercise (generally walking), of moderate intensity and comparatively low frequency (which is associated with better maintenance), as well as frequent professional contact.22 The major limitation of this study was its reliance on self-report, as patients over 65 years tend to overestimate their physical activity.12 The number of participants and limited resources precluded general use of more objective measures of physical activity or fitness. Objective measurements of energy expenditure by accelerometer in 59 volunteers did not detect a difference between the control and intervention groups, possibly because of the small sample size. Other possible reasons are that people in each group who had established regular physical activity volunteered preferentially for accelerometer measurement, or that the self-reported increase in physical activity in the intervention group was not real. We were also unable to detect any differences between the intervention and control groups in cardiovascular risk factors after 12 months. This is consistent with results of others. For example, patients referred by their GPs to a local leisure centre had increased self-reported physical activity after 37 weeks, but no changes in systolic or diastolic blood pressures or body mass index.23 In our study, the increase in self-reported physical activity in the intervention group was possibly not large enough to increase physical fitness. Previous investigators have shown that cardiovascular risk factors are more strongly related to physical fitness than to physical activity,4,5and that, in individuals with low levels of fitness, increased physical activity without a change in fitness does not modify cardiovascular risk factors.24 Further, although the difference in physical activity between the intervention and control groups reached statistical significance, it was modest in absolute terms. Finally, all participants remained under the usual care of their GPs, who were free to initiate or cease prescribing medications that might modify cardiovascular risk factors. We found declines in quality of life from baseline to 12 months in both groups, with the greatest change in the first three months. We hypothesise that quality of life was more accurately reported at three months than at baseline, when scores were much higher than the Australian norms for the participants' age. It is possible that participants were initially keen to present themselves as healthy in all respects or that they were expressing high hopes for the study. In conclusion, this study showed that, for a specific population of general practice patients, providing physical activity advice three-monthly for six months resulted in increases to both self-reported physical activity and intention to exercise, which were maintained at 12-month follow-up. Further research in primary care is needed to determine whether these changes apply to other groups and whether they confer significant health benefits. Acknowledgements This project was funded by a Public Health Research and Development Project Grant from the National Health and Medical Research Council and Department of Health, Housing, Local Government and Community Services. We wish to thank the GPs and staff from Blackwood and Flinders Clinics, Adelaide, SA, for their assistance and Lynne Giles (Flinders University, Adelaide, SA) for statistical advice. Conflict of interest: None. References Paffenbarger RS, Hyde RT, Wing AL, et al. The association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med 1993; 328: 538-545. Blair SN, Kohl HW, Paffenbarger RS, et al. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989; 262: 2395-2401. Folsom AR, Caspersen CJ, Taylor HL, et al. Leisure time physical activity and its relationship to coronary risk factors in a population-based sample. Am J Epidemiol 1985; 121: 570-579. Eaton CB, Lapane KL, Garber CE, et al. Physical activity, physical fitness and coronary heart disease risk factors. Med Sci Sports Exerc 1995; 27: 340-346. Lochen M-L, Rasmussen K. The Tromso study: physical fitness, self-reported physical activity, and their relationship to other coronary risk factors. J Epidemiol Community Health 1992; 26: 103-107. Active Australia. Physical activity levels of Australians. Results of the Active Australia baseline survey 1997. Available at <www.ausport.gov.au/ partic/actozfr.html> Bull FCL, Schipper ECC, Jamrozik K, Blanksby BA. Beliefs and behaviour of general practitioners regarding promotion of physical activity. Aust J Public Health 1995; 19: 300-304. Murphy B, Ruth D. GPs role in CVD Prevention. A report on focus group discussions with general practitioners for the RISK study in general practice. Melbourne: Monash University, 1991. Bull FCL, Schipper ECC, Jamrozik K, Blanksby BA. How can and do Australian doctors promote physical activity? Prev Med 1997; 26: 866-873. Eaton CB, Menard LM. A systematic review of physical activity promotion in primary care settings. Br J Sports Med 1998; 32: 11-16. Harland J, White M, Drinkwater C, et al. The Newcastle exercise project: a randomised controlled trial of methods to promote physical activity in primary care. BMJ 1999; 319: 828-832. Sims J, Smith F, Duffy A, Hilton S. The vagaries of self-report of physical activity: a problem revisited and addressed in a study of exercise promotion in the over 65s in general practice. Fam Prac 1999; 16: 152-157. Simmonds GJ, Naylor P-J, Riddoch CJ, Velleman G. Stage-based counselling for exercise in primary care -- a controlled trial. Presented at the Scientific Basis of Health Services Conference. 1995 Oct; London. Halbert JA, Silagy CA, Finucane P, et al. Recruitment of older adults for a randomized, controlled trial of exercise advice in a general practice setting. J Am Geriat Soc 1999; 47: 477-481. Marcus BH, Banspach SW. Using the stages of change model to increase the adoption of physical activity among community participants. Am J Health Promot 1992; 6: 424-429. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 health survey manual and interpretation guide. Boston: New England Medical Center, 1993. National Institutes of Health Consensus Development Panel on Physical Activity and Cardiovascular Health. Physical activity and cardiovascular health. JAMA 1996; 276: 241-246. American College of Sports Medicine. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness in healthy adults. Position Stand. Med Sci Sports Exerc 1990; 22: 265-274. Jacobs DR, Ainsworth BE, Hartman TJ, Leon AS. A simultaneous evaluation of 10 commonly used physical activity questionnaires. Med Sci Sports Exerc 1993; 25: 81. Liang K-Y, Zeger S. Longitudinal data analysis using generalized linear models. Biometrika 1986; 73: 13-22. Stevens W, Hillsdon M, Thorogood M, McArdle D. Cost-effectiveness of a primary care based physical activity intervention in 45-74 year old men and women: a randomised controlled trial. Br J Sports Med 1998; 32: 236-241. Hillsdon M, Thorogood M, Anstiss T, Morris J. Randomized controlled trials of physical activity promotion in free living populations: a review. J Epidemiol Community Health 1995; 49: 448-453. Taylor AH, Doust J, Webborn N. Randomised controlled trial to examine the effects of a GP exercise referral programme in Halisham, East Sussex, on modifiable coronary heart disease risk factors. J Epidemiol Community Health 1998; 52: 595-601. McMurray RG, Ainsworth BE, Harrell JS, et al. Is physical activity or aerobic power more influential on reducing cardiovascular disease risk factors? Med Sci Sports Exerc 1998; 30: 1521-1529. (Received 4 Feb, accepted 4 May, 2000) Authors' details Department of Rehabilitation and Aged Care, Flinders University of South Australia, Adelaide, SA. Julie A Halbert, MSc, Research Manager; Paul M Finucane, FRCPI, FRACP, Head. Monash Medical Centre, Melbourne, VIC. Christopher A Silagy, PhD, FRACGP, FAFPHM, Head of Institute of Public Health and Health Services Research. School of Education, Flinders University of South Australia, Adelaide, SA. Robert T Withers, PhD, FASMF, FACSM, Senior Lecturer in Rehabilitation. Hampstead Centre, Royal Adelaide Hospital, Adelaide, SA. Phil A Hamdorf, PhD, Head of Centre for Physical Activity in Ageing. Reprints will not be available from the authors. Correspondence: Ms J A Halbert, Department of Rehabilitation and Aged Care, Repatriation General Hospital, Daw Park, SA 5041. julie.halbertATflinders.edu.au Make a comment 1: Clinical measures at baseline and 12-month follow-up (mean and 95% confidence interval) Control group (n=150) Intervention group (n=149) Baseline 12 months Baseline 12 months Body weight (kg) Height (cm) Resting heart rate (bpm) 74.0 (71.8-76.1) 165.8 (164.4-167.2) 71.3 (69.7-72.9) 73.6 (71.5-75.8) ND 71.6 (70.0-73.2) 75.9 (73.8-78.0) 166.9 (165.5-168.4) 70.9 (69.1-72.6) 76.0 (73.9-78.1) ND 71.1 (69.6-72.6) Blood pressure (mm Hg) Systolic Diastolic 148.1 (145.1-151.0) 85.7 (84.2-87.1) 146.6 (143.4-149.6) 86.3 (84.9-87.7) 148.6 (145.9-151.4) 85.6 (84.1-87.1) 147.4 (144.4-150.5) 86.1 (84.6-87.7) Serum levels (mmol/L) Total cholesterol Triglycerides HDL cholesterol LDL cholesterol 5.88 (5.73-6.03) 1.64 (1.50-1.78) 1.34 (1.27-1.40) 3.81 (3.67-3.95) 5.70 (5.55-5.85)* 1.57 (1.43-1.70)* 1.34 (1.28-1.41) 3.65 (3.52-3.80)* 5.85 (5.68-6.02) 1.70 (1.50-1.89) 1.30 (1.24-1.37) 3.78 (3.65-3.95) 5.63 (5.47-5.80)* 1.57 (1.42-1.73)* 1.29 (1.23-1.35) 3.64 (3.50-3.79)* *Significant decrease from baseline level (P<0.05). HDL=high-density lipoprotein. LDL=low-density lipoprotein. ND=measurement not done. Back to text 2: Self-reported physical activity at baseline and follow-up (median value and 25th-75th percentile) Control group (n=150) Intervention group (n=149) Baseline 3 months 6 months 12 months Walking Frequency (sessions/week) Time (mins/session) 0 (0-2) 0 (0-20) 2 (0-3)* 30 (0-49)* 2 (0-4)* 30 (0-60)* 2 (1-3)* 30 (10-60)* Vigorous exercise Frequency (sessions/week) Time (mins/sessions) 0 (0-0) 0 (0-0) 0 (0-1)* 0 (0-16)* 0 (0-2)* 0 (0-21)* 0 (0-1)* 0 (0-15)* Walking Frequency (sessions/week) Time (mins/session) 0 (0-1) 0 (0-25) 3 (1-4)*† 30 (19-50)* 3 (2-4)*† 30 (20-60)* 3 (1-4)*† 30 (10-60)* Vigorous exercise Frequency (sessions/week) Time (mins/sessions) 0 (0-0) 0 (0-0) 2 (0-3)*† 20 (0-35)*† 2 (0-3)*† 20 (0-40)*† 2 (0-3)*† 20 (0-35)*† *Statistically significant increase from baseline level (P<0.05). †Values significantly higher than for control group (P<0.05). Back to text Back to text

Julie A Halbert · Christopher A Silagy · Paul M Finucane · Robert T Withers · Phil A Hamdorf

Indigenous Health Research Reducing premature death and renal failure in Australian Aboriginals A community-based cardiovascular and renal protective program Wendy E Hoy, Philip R Baker, Angela M Kelly and Zhiqiang Wang MJA 2000; 172: 473-478 Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Aboriginal health Abstract Objective: To describe results of a systematic treatment program to modify renal and cardiovascular disease in an Aboriginal community whose rates of renal failure and cardiovascular deaths are among the highest in Australia. Design: Longitudinal survey of people during treatment, and comparison of rates of natural death and renal failure with those in a historical control group. Setting: Tiwi Islands (population, about 1800), November 1995 to December 1998. Participants: All adults with blood pressure ≥ 140/90, with diabetes and urinary albumin/creatinine ratio (ACR) ≥ 3.4 g/mol (microalbuminuria threshold), or with progressive overt albuminuria (ACR ≥ 34 g/mol) were eligible for treatment. The historical control group comprised 229 people who satisfied these criteria in the pretreatment period 1992-1995. Interventions: Perindopril, combined with calcium-channel blockers and diuretics if needed to achieve blood pressure goals; attempts to improve control of blood glucose and lipid levels; health education. Main outcome measures: Blood pressure, ACR, serum creatinine level and glomerular filtration rate (GFR) over two years of treatment; rates of renal failure and natural death compared with control group (analysed on intention-to-treat basis). Results: 258 people enrolled in the program, and 118 had complete data for two years of treatment. In these 118, blood pressures fell significantly, while ACR and GFR stabilised. Rates of the combined endpoints of renal failure and natural death per 100 person-years were 2.9 for the treatment group (95% CI, 1.7-4.6) and 4.8 for the control group (95% CI, 3.3-7.0). After adjustment for baseline ACR category, the relative risk of the treatment group versus the control group for these combined endpoints was 0.47 (95% CI, 0.25-0.86; P = 0.013). Treatment benefit was especially marked in people with overt albuminuria or hypertension and in non-diabetic people. The estimates of benefit were supported by a fall in community rates of death and renal failure. Conclusions: Aboriginal people can participate enthusiastically in chronic disease management, with rapid, dramatic improvement in clinical profiles and mortality. Similar programs should be introduced urgently into other Aboriginal communities nationwide. Aboriginal people in the Northern Territory are experiencing an epidemic of cardiovascular disease (CVD) and end-stage renal disease (ESRD). Age-standardised CVD death rates are three times those of non-Aboriginal people,1 while the incidence of treated ESRD in Aboriginal people is approaching 1000 per million, and doubling every four years.2 ESRD treatment costs, at $100 000 per person annually, are becoming a huge burden,3 but premature death is the greater human catastrophe. These problems are especially serious in the communities of the Tiwi Islands, north of Darwin (population, about 1800) (Box 1). The incidence of ESRD among Tiwi people recently reached 2700 per million, and they have one of the highest CVD mortality rates in Australia.2,4In a community-wide screening program starting in the early 1990s, we found a high prevalence of cardiovascular risk factors, including type 2 diabetes and hypertension, and albuminuria (measured by the albumin/creatinine ratio (ACR) of a random urine specimen).5 Albuminuria correlated inversely with glomerular filtration rate (GFR), and its intensity predicted not only renal failure, but also cardiovascular deaths and all-cause natural deaths.6-9 In the early 1990s, use of antihypertensive drugs was increasing gradually in the Tiwi communities, but systematic management of the huge burden of morbidity identified by the screening program was beyond the capacity of the existing health services. In November 1995, we therefore introduced a systematic treatment program to reduce blood pressure and to modify the expression and progression of renal and cardiovascular disease. We describe the results of this program to the end of 1998. Methods The study was a longitudinal survey of people in the Tiwi Islands communities during treatment, and comparison of endpoints with a historical control group. Treatment was offered to eligible people as part of improved standard care. All participants gave informed consent to have their course followed up for the projects The epidemiology and prevention of Aboriginal renal disease, Parts 1 and 2. These projects were approved by the Joint Institutional Ethics Committee of the Menzies School of Health Research and Territory Health Services, Darwin, and its Aboriginal subcommittee, and by the Tiwi Land Council (Part 1) and the Tiwi Health Board (Part 2). Treatment program The program relied considerably on screening and treatment algorithms. Interventions included education about diet, exercise, health behaviours and medical treatment. Medical treatment centred around use of a long-acting angiotensin-converting enzyme inhibitor (ACEi) (perindopril; Coversyl [Servier]), aggressive blood pressure control,10,11 and, where appropriate, oral hypoglycaemic and lipid-lowering drugs. The choice of an ACEi was based on the well recognised antihypertensive and cardiovascular-protective effects of this class of drug12 and several reports, subsequently substantiated, of an additional renal protective effect.13-23 If antihypertensive drugs had been prescribed before entry into the study, they were discontinued or tapered when perindopril was started. Objectives were to achieve a minimum daily dose of 4 mg perindopril and to lower blood pressure, initially to < 130/85, but more recently to < 120/75.10 A stepped approach to achieve these blood pressures included increasing perindopril to 8 mg, with addition of long-acting calcium-channel blockers and/or diuretics if needed. Participants were seen at least monthly while medications were introduced or changed, then at least every three months for the first year, and at least every six months thereafter. Each examination included a minimum of a brief history, medication review, and measurement of weight, blood pressure, urinary ACR and serum creatinine level and, in diabetics, evaluation of blood glucose control. After a start-up period, the day-to-day program was largely conducted by local health workers and community project officers, who were supported by telephone contacts and regular visits by nurse coordinators from Darwin. Doctors, who reviewed eligibility assessments, supported or made treatment decisions and modified the protocols, were less intensively involved. The program has run in parallel with other clinic activities in Nguiu, Bathurst Island, but has been integrated into regular clinic activities at the Melville Island communities of Milikapiti and Pirlangimpi. Participants Treatment group: People eligible for ACEi therapy were those with: hypertension (blood pressure ≥ 140/90 mmHg); diabetes and ACR ≥ 3.4 g/mol (microalbuminuria threshold), regardless of blood pressure; or progressive overt albuminuria (ACR ≥ 34 g/mol on first testing and increasing over time), regardless of blood pressure or diabetes status. All qualifying features needed to be confirmed on at least two occasions. People with past adverse reactions and breastfeeding women were ineligible for ACEi therapy. Fertile women were advised about teratogenic risks and the options of contraception or discontinuation of ACEi medication early in unplanned pregnancy. People with serum creatinine levels over 250 µmol/L were considered ineligible for long-acting ACEi therapy in the first six months of the program, but were later enrolled when treatment proved safe and effective in people with mild and moderate renal insufficiency. To some extent, enrolment was prioritised by disease severity. Thus, most people with overt albuminuria, uncontrolled blood pressure and renal insufficiency were enrolled in the first year of the program. Control group: In the absence of a parallel control group, rates of renal failure and natural death in participants were compared with those of a historical control group from the pre-program period. This control group comprised adults whose results on a single screening examination between July 1992 and September 1995 met the eligibility criteria later used for the treatment program. Selection was blinded to their future course, which was followed to 30 October 1995. Data analyses Analyses were performed using STATA statistical software.24 Clinical profiles in the treatment group were described at baseline, six, 12, and 24 months of treatment, regardless of compliance, and were compared by analysis of variance, using geometric means for ACR and serum creatinine level to normalise their distribution. All endpoint data in the treatment group were analysed on an intention-to-treat basis. Rates of natural death and renal failure were calculated by baseline ACR category for the intention-to-treat and control groups, and the risk ratios for the intention-to-treat group calculated in stratified analysis by ACR category by the Mantel-Haenszel method for cohort studies. Kaplan-Meier survival curves for both groups were derived, and survivals compared by the non-parametric Wilcoxon technique. Results Enrolment By 31 December 1998, 258 people had enrolled in the program (29% of all adults in the island communities) and 227 were still participating. Of these, 39 had completed over three years of treatment, 137 over two years, 168 over one year, and 192 over six months. Of 31 dropouts, nine had died, seven had begun dialysis (two of whom later died), seven had stopped taking the medication because of side effects (cough in four; angioedema, itching and dizziness in one each), four became normotensive without treatment, two chose to quit, one moved, and one entered palliative care with osteomyelitis of the skull. Characteristics of people who enrolled are shown in Box 2: 42% had diabetes, almost two-thirds had hypertension, with a quarter already prescribed enalapril, and almost two-thirds had overt albuminuria. Medications and participation Doses of perindopril prescribed for the 227 people participating at the end of 1998 were 2 mg (5 people; 2%), 4 mg (72; 32%), and 8 mg (150; 66%). Calcium-channel blockers were being taken by 37 people (16%), diuretics by 15 (7%), and both by 13 (6%). Participation was enthusiastic, and compliance increased over time; 65% were taking ≥ 70% of their prescribed dose (assessed by pill counts and interview), 27% were taking medicine occasionally, and 7% were taking little or no medication at the end of 1998. Two-year clinical profiles Of the 137 people who had been treated for at least two years, 118 had largely complete follow-up data and were included in the two-year profile. These 118 were well matched with participants not included in this profile for age, BMI, and blood pressure, but were more likely to have diabetes, overt albuminuria, and to have been taking prior ACEi therapy (Box 2). These differences reflected prioritisation of sicker people for early entry into the program. Two-year clinical profiles for the 118 people are shown in Box 3. Treatment was associated with a swift and sustained fall in blood pressure, as well as stabilisation of ACR and GFR. Results are presented according to participants' clinical categories at baseline in Box 4. The fall in blood pressure was marked in people with hypertension at baseline and less marked but still apparent in those who had been normotensive, as well as in those previously prescribed an ACEi. Good blood pressure responses were seen in people both with and without diabetes, those with micro- and overt albuminuria and those with "normal" and raised levels of serum creatinine. Stabilisation of ACR and GFR was seen in all clinical categories. Indeed, serum creatinine level tended to fall and GFR to rise in all categories. Baseline weight did not change (mean, 74 kg; SD, 16 kg), while mean serum potassium level rose non-significantly from 4.04 mmol/L (SD, 0.46 mmol/L) to 4.14 mmol/L (SD, 0.49 mmol/L). No one developed significant hyperkalaemia. There was no evidence that ACEi therapy accelerated progression to renal insufficiency. Comparisons with control group Two hundred and twenty-nine people qualified as controls from the pre-program period, comprising 123 people who subsequently went onto the treatment program and 106 people who did not. Reasons for not going onto the program included death, dialysis, failure to qualify on subsequent examinations, presence of exclusion criteria (eg, pregnancy, breastfeeding), declining treatment, or moving. Baseline characteristics of the control and intention-to-treat groups are compared in Box 2. The control group was younger at enrolment, had lower BMI, and included fewer people with diabetes or overt albuminuria. The control group was followed up for a total of 564 years (individual mean, 2.5 years; range, 1 month to 3.3 years) and the intention-to-treat group for 560 years (individual mean, 2.2 years; range, 2 weeks to 3.1 years). Endpoints of the two groups are compared in Box 5. The treatment group as a whole had lower rates of dialysis, natural death and the combined endpoint (dialysis or death) than the control group, although the differences were not significant. However, rates of endpoints were strongly correlated with baseline ACR category. Indeed, renal failure necessitating dialysis was confined to people with ACR ≥ 100 g/mol at baseline, and in these people the treatment group had an estimated 57% lower dialysis rate than the control group. In contrast, rates of natural death and of the combined endpoint were lower in the treatment group than in the control group for all categories of baseline overt albuminuria. After adjustment for ACR category, the treatment group had an estimated 45% lower rate of natural death and an estimated 53% lower rate of the combined endpoint. Box 6 shows estimates of the survival advantage in people with various baseline clinical profiles after adjustment for ACR category. Treatment benefit was strong in people with overt albuminuria, non-diabetic people and people with hypertension. It was less marked in diabetic or normotensive people. Survival estimates for people with overt albuminuria at baseline are shown in Box 7. Although the intention-to-treat group showed attrition during the first year (representing ESRD and deaths of seriously ill people prioritised for early entry), a survival advantage over the control group was clear by two years of the treatment program. Discussion This study found that the introduction of a systematic treatment program to the Tiwi Island communities was associated with marked improvements in blood pressure and stabilisation of renal function in people receiving treatment. These changes contrasted sharply with the increase in blood pressure and ACR and fall in GFR noted previously in people matched for ACR category in the pretreatment status quo.10 The treatment program was also associated with a swift and dramatic decrease in rates of renal failure and natural death in the treated group compared with a historical control group, suggesting that the program prevented or at least delayed these outcomes. Further evidence for the existence of this estimated survival benefit was the decrease in community-wide rates of ESRD and natural death -- previously increasing -- after introduction of the program (Box 8). In contrast, ESRD continued to increase among non-Tiwi Aboriginal people in the Top End (Box 9), arguing against a chance background effect. Preliminary estimates of cost effectiveness of the program, based solely on avoidance or delay of dialysis, are already startling.3,25 These results show that Aboriginal people are interested in health issues and receptive to health messages, and will take medications over the long term to protect against future health risk, with excellent response. They also show that a systematic approach, with testing and treatment algorithms and clear goals, is superior to the previous approach of gradually improving medical management. While we cannot apportion relative benefit to individual elements of the treatment program, the observed fall in blood pressures alone would be expected to markedly reduce cardiovascular deaths and progression of renal disease,10,11 compatible with the effects we found. Our intention-to-treat analyses probably underestimate the therapeutic efficacy of treatment, as a third of the intention-to-treat group took the prescribed medications only occasionally or not at all. Use of the historical control group was also a potential source of bias. On the one hand, it may have also led to underestimates of treatment benefit because of the group's potentially better survival prospects, based on its younger mean age, milder disease and the probable inclusion of people with borderline blood pressure or ACR readings, as eligibility for the group was not confirmed by a second examination. On the other hand, the 123 controls who subsequently entered the treatment program might have had superior survival characteristics to the controls who did not enter the program, potentially inflating the apparent benefit of the program. Another source of bias was the prioritisation of the sickest people for early enrolment in the treatment program, many of whom were failing previous management regimens. This predisposes to poor short term outcomes of the program and underestimates of its benefits. Analyses of program results at four and five years, when more people have passed through one to two years of treatment, will dilute the impact of these early events. Longer-term analyses will also be needed to evaluate any survival effect of treatment in people without overt albuminuria, and the extent to which treatment has delayed rather than prevented ESRD and death in people with overt albuminuria. The program could still be improved. Blood pressure control should be better; at two-year follow-up, 31% of people had blood pressures ≥ 140/90, and 50% had blood pressures ≥ 120/75.10 Hypertension, and therefore eligibility for treatment even in the absence of albuminuria, should probably be redefined as blood pressures ≥ 130/80 in this high-risk population.10 Control of blood glucose and lipid levels needs to improve. Finally, we might reassess the notions of the maximally renal-protective dose of ACEi and/or add other renal-protective drugs, such as angiotensin II receptor blocking agents,26,27 for poor responders. Much of the success of this particular program derives from a strong sense of community ownership and control, a non-judgemental, non-authoritarian style, and respect for competing personal and community perspectives and priorities. Individuals appreciate personalisation of their health goals, and many are slowly adopting lifestyle changes. This program is now being integrated into normal clinic activities at Nguiu. Its protocols have also been incorporated into standard care guidelines for Aboriginal adults in the Top End of the NT.28 Extension of its principles to other Aboriginal communities with high burdens of disease nationwide is a matter of urgency.29 Allocation of adequate resources is a challenge, but the clinical benefit and cost-effectiveness mandate the short- and intermediate-term investment. Acknowledgements This study was supported by Servier Australia, the Australian Kidney Foundation, Rio Tinto, the National Health and Medical Research Council, the Stanley Tipiloura Fund, and Territory Health Services. We gratefully acknowledge the support, enthusiasm and participation of the Tiwi community and the staff of the Tiwi Island clinics at Nguiu, Milikapiti and Pirlangimpi. We especially thank the Tiwi Health Board for review of this manuscript, and Treatment Program Coordinators Susan Jacups and Kiernan McKendry, Aboriginal Health Workers Jerome Kerinauia and Nellie Punguatji, and Community Project Officers Eric Tipiloura and Elizabeth Tipiloura for their dedicated work. Finally, we thank Resident Medical Officer, Dr Chris Harrison, for his support and participation. Dr Alan Cass updated the Top End ESRD rates. References Cunningham J, Condon J. Premature mortality in Aboriginal adults in the Northern Territory. Med J Aust 1996; 165: 309-312. Spencer JS, Silva D, Hoy WE. An epidemic of renal failure among Australian Aborigines. Med J Aust 1998; 168: 537-541. You J, Hoy W, Beaver C, Zhao Y. Costs of hemodialysis and hospitalisations for patients with end stage renal disease in the Top End of the Northern Territory. Presented at the 35th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology; 1999 Mar 3-5; Brisbane (Qld). Jain SK, editor. Trends in mortality by causes of death in Australia, the States and Territories during 1971-1992, and in statistical subdivisions during 1991-1992. Canberra: National Center for Epidemiology and Population Health and Australian Bureau of Statistics, 1994. (ABS catalogue no. 3313.0)Hoy WE, Pugsley DJ, Normal RJ, Hayhurst BG. A brief heath profile of adults in a Northern Territory Aboriginal community: with an emphasis on preventable morbidities. Aust N Z J Public Health 1997; 21: 121-126. Hoy WE, Mathews JD, Pugsley DJ, et al. The multidimensional nature of renal disease: rates and associations of albuminuria in a high risk Aboriginal community. Kidney Int 1998; 54: 1296-1304. Cockcroft D, Gault MK. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41. Hoy WE, Wang Z, Baker P, et al. The natural history of renal disease in an Australian Aboriginal community. Presented at the 35th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology; 1999 Mar 3-5; Brisbane (Qld). McDonald S, Wang Z, Hoy WE. Physical and biochemical predictors of death in an Australian Aboriginal cohort. Clin Exp Pharmacol Physiol 1999; 26: 618-621. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997; 157: 2413-2446. Collins R, Peto R, MacMahon S. Blood pressure, stroke and coronary artery disease. Part 2. Short term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335: 827-838. Lonn EM, Yusuf S, Jha P. Emerging role of angiotensin converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994; 90: 2056-2068. Mogensen CE. Angiotensin converting enzyme inhibitors and diabetic nephropathy. BMJ 1992; 304: 327-328. Ravid M, Savin H, Lang R, et al. Proteinuria, renal impairment, metabolic control, and blood pressure in type 2 diabetes mellitus. A 14-year follow up report on 195 patients. Arch Intern Med 1992; 152: 1225-1229. Ravid M, Savin H, Jutrin I, et al. Long term stabilizing effect of angiotensin converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type 2 diabetic patients. Ann Intern Med 1993; 118: 577-581. Gansevoort RT, de Zeeuw D, de Jong PE. Long term benefits of the antiproteinuric effect of angiotensin converting enzyme inhibition in nondiabetic renal disease. Am J Kidney Dis 1993; 22: 202-206. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456-1462. Bedogna V, Valvo E, Casagrande P, et al. Effect of ACE inhibition in normotensive patients with chronic glomerular disease and normal renal function. Kidney Int 1994; 38: 101-107. Cattran DC, Greenwood C, Ritchie S. Long term benefits of angiotensin converting enzyme inhibitor therapy in patients with severe immunoglobulin A nephopathy: a comparison to patients receiving treatment with other antihypertensive agents and patients receiving no therapy. Am J Kidney Dis 1994; 23: 247-254. Mogensen CE, Keane WF, Bennett PH, et al. Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet 1995; 346: 1080-1084. Maschio G, Alberti D, Janin G, et al. Effect of angiotensin converting enzyme inhibitor benazapril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334: 939-945. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, nondiabetic nephropathy. Lancet 1997; 349: 1857-1863. Ruggenenti P, Perna A, Gheradi G, et al. Renoprotective properties of ACE inhibition in nondiabetic nonnephrotic proteinuria. Lancet 1999; 354: 359-364. Statcorp. Stata statistical software, release 6.0. College Station (TX): Stata Corporation, 1999. Baker P, Hoy WE, Wang Z, et al. Towards evaluation of the cost-effectiveness of a treatment program for renal disease in Australian Aborigines. Presented at the 35th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology; 1999 Mar 3-5; Brisbane (Qld). Mackenzie HS, Ziai F, Omer SA, et al. Angiotensin receptor blockers in chronic renal disease: the promise of a bright future. J Amer Soc Nephrol 1999; 10 Suppl 12: S283-S286. Mimran A, Ribstein J. Angiotensin receptor blockers: pharmacology and clinical significance. J Amer Soc Nephrol 1999; 10 Suppl 12: S273-S277. Hoy WE. Screening and treatment for renal disease: the community model. Nephrology 1998; 4 Suppl iii-iv: S90-S95. Minutes of the Inaugural Meeting of the National Aboriginal and Torres Strait Islander Renal Disease Scientific Working Group and its Guidelines Subcommittee. Office of Aboriginal and Torres Strait Islander Health. 1999; Nov 16 Alice Springs (NT). (Received 14 Jul 1999, accepted 6 Apr 2000) Authors' details Menzies School of Health Research, Darwin, NT. Wendy E Hoy, FRACP, Senior Renal Consultant; Philip R Baker, BSc, NHMRC PhD Student, Menzies School of Health Research, and Department of Social and Preventive Medicine, University of Queensland, Brisbane, QLD; Angela M Kelly, RN, BAppSc, Senior Program Coordinator; Zhiqiang Wang, PhD, Epidemiologist and Statistician, and Senior Research Officer. Reprints will not be available from the authors. Correspondence: Dr W E Hoy, Menzies School of Health Research, PO Box 41096, Casuarina, NT, 0811. wendyATmenzies.su.edu.au Make a comment Back to text 2: Baseline characteristics of participants in the treatment program and the historical control group All participantsIncluded in 2-year profiles Historical control group (n=258)Yes (n=118)No* (n=140)(n=229)P?% Men43%47%40%51%0.13Mean age in years (SD)43.4 (11.1)43.5 (10.4)43.4 (11.7)40.8 (12.8)0.02Mean body mass index27.0 (5.7)27.1 (5.7)27.0 (5.8)25.2 (5.4)< 0.001(kg/m2) (SD) Blood pressure (mm Hg) Mean systolic (SD)135 (20)135 (20)135 (21)134 (20)0.58Mean diastolic (SD)82 (14)81 (13)82 (15)85 (15)0.01% With hypertension?65%66%63%65%0.91% With diabetes42%46%37%26%0.001% With ACR ≥34g/mol65%74%58%58%0.02% With raised serum creatinine level§12%13%11%12%0.62Previous ACEi25%33%16%NR ACR=urinary albumin/creatinine ratio. ACEi=angiotensin-converting enzyme inhibitor. NR=no result. *90 had been enrolled less than 2 years, 19 had been enrolled ≥ 2 years but did not have complete data for all visits, and 31 had dropped out. ?For test of significance of difference between all participants (intention-to-treat group) and control group. ?Blood pressure ≥140/90 or taking antihypertensive treatment. §Serum creatinine level > 106µmol/L (women), > 120µmol/L (men). Back to text 3: Clinical profiles over two years of treatment in 118 Tiwi people VariableBaseline6 months12 months24 monthsP*Blood pressure (mm Hg) Mean systolic (SD)135 (20)126 (21)124 (20)122 (22)< 0.001Mean diastolic (SD)81 (13)75 (14)77 (14)74 (14)< 0.001Mean? ACR (g/mol) (95% CI)55 (43-70)50 (39-64)53 (41-69)55 (43-69)0.36Mean? serum creatinine level (µmol/L) (95% CI)89 (85-93)88 (84-92)88 (84-92)84 (79-89)0.44Mean GFR (mL/min/1.73m2) (SD)89 (26)91 (28)89 (26)93 (29)0.54ACR=urinary albumin/creatinine ratio. GFR=glomerular filtration rate. *Test for significance of difference in values among the four intervals by analysis of variance. ?Geometric mean. Back to text 4: Clinical profiles over two years of treatment in 118 Tiwi people, by clinical category at baseline Blood pressure PreviousDiabetes < 140/90 (n=69)≥ 140/90 (n=49)ACEi (n=39)No (n=64)Yes (n=54)BP (mm Hg) Mean systolicBaseline123 (11)152 (17)136 (19)135 (21)136 (19)(SD)24 months117 (20)130 (22)128 (23)122 (15)122 (23)Mean diastolicBaseline75 (9)90 (12)83 (11)81 (15)81 (10)(SD)24 months72 (14)77 (13)78 (14)76 (15)72 (11)Mean ACRBaseline66 (50-87)43 (27-61)62 (40-97)48 (34-68)62 (45-91)(g/mol) (95% CI)24 months75 (57-98)35 (23-54)66 (45-98)50 (36-70)60 (41-87)Mean serumBaseline88 (82-94)90 (85-95)94 (85-103)90 (85-95)87 (81-93)creatinine level (µmol/L) (95% CI)24 months84 (77-92)84 (77-91)93 (82-105)83 (77-89)86 (78-94)Mean GFR (SD)Baseline91 (29)86 (21)91 (31)90 (26)88 (26)(mL/min/1.73m2)24 months95 (32)91 (25)92 (32)96 (28)90 (24) Albuminuria Serum creatinine level Micro-* (n=28)Overt? (n=86)Normal (n=98§)Raised? (n=15§)BP (mm Hg)Mean systolicBaseline 134 (24)135 (18)135 (20)139 (19)(SD)24 months 123 (23)120 (21)123 (22)118 (20)Mean diastolicBaseline 82 (15)81 (12)82 (13)78 (13)(SD)24 months 73 (15)74 (14)75 (14)71 (13)Mean ¶ ACRBaseline 16 (13-19)104 (90-121)49 (38-65)125 (83-187)(g/mol) (95% CI)24 months 19 (15-25)90 (72-112)50 (38-66)88 (45-174)Mean¶ serumBaseline 85 (79-92)90 (85-95)83 (82-88)137 (123-153)creatinine level (µmol/L) (95% CI)24 months 75 (70-81)88 (82-95)78 (75-81)119 (98-144)Mean GFR (SD)Baseline 88 (23)89 (28)95 (23)55 (18)(mL/min/1.73m2)24 months 102 (24)91 (28)99 (24)57 (30) ACEi=angiotensin-converting enzyme inhibitor. BP=blood pressure. ACR=urinary albumin/creatinine ratio. GFR=glomerular filtration rate. *ACR, 3.4-33g/mol. ?ACR >34g/mol. ?Serum creatinine level >106µmol/L (women), >120µmol/L (men). §Data not available for all participants. ¶Geometric mean. Back to text 5: Rates of endpoints in historical control and intention-to-treat groups Historical control group (n=229) BaselineEndpointACR (g/mol)CasesPerson-yearsRate per 100 person-years (95% CI)DialysisAll ≥ 1009 9564 1201.6 (0.8-3.1) 7.5 (3.9-14.4)Natural deathAll < 34 34-99 ≥ 10018 2 9 7555 226 205 1243.2 (1.0-5.1) 0.9 (0.2-3.5) 4.4 (2.2-8.4) 5.6 (2.7-11.2)Combined (dialysis or natural death)All < 34 34-99 100-199 ≥ 20026? 2 9 6 9543 227 205 74 374.8 (3.3-7.0) 0.9 (0.2-3.5) 4.4 (2.3-8.4) 8.1 (3.6-18.0) 24.2 (12.6-46.5) Intention-to-treat group (n=258) Endpoint CasesPerson-yearsRate per 100 person-years (95% CI)Dialysis 7 7548 1971.3 (0.6-2.6) 3.6 (1.7-7.0)Natural death 11 3 3 5560 178 194 1882.0 (1.1-3.4) 1.7 (0.5-5.2) 1.5 (0.4-4.8) 2.7 (1.1-6.4)Combined (dialysis or natural death) 16 3 3 3 7549 178 193 104 732.9 (1.7-4.6) 1.7 (0.5-5.2) 1.6 (0.5-4.8) 2.9 (0.9-8.9) 9.6 (4.6-20.2) Relative risk (RR) (95% CI) Endpoint Crude*Adjusted?P (for adjusted RR)Dialysis 0.77 (0.24-2.33)0.43 (0.17-1.12)0.08Natural death 0.59 (0.25-1.31)0.55 (0.26-1.16)0.11Combined (dialysis or natural death) 0.59 (0.30-1.14)0.47 (0.25-0.86)0.01 ACR=urinary albumin/creatinine ratio. *Overall estimate for treatment group versus control group. ?Relative risk adjusted for baseline ACRcategory. ?People who underwent dialysis and later died were counted only once for the combined endpoint. Back to text 6: Estimated survival advantage for intention-to-treat versus control group, adjusted for ACR category Clinical category at baselineRelative risk (95% CI)?PAll0.47 (0.25-0.86)0.01Overt albuminuria0.36 (0.18-0.72)0.004DiabetesNo0.28 (0.09-0.93)0.02Yes0.65 (0.28-1.51)0.31HypertensionNo0.59 (0.25-1.44)0.24Yes0.38 (0.15-0.98)0.04* ACR=urinary albumin/creatinine ratio. Categories: < 3.4 3.4-33, 34-99, 100-199, ≥ 200 g/mol. ? For combined endpoints of natural death and renal failure, intention-to-treat versus control group. Back to text Back to text Back to text Back to text

Wendy E Hoy · Philip R Baker · Angela M Kelly · Zhiqiang Wang

Abstract Objectives: To compare rates of mortality from coronary heart disease (CHD) between populations living within and outside Australian capital city statistical divisions. Design and setting: Descriptive epidemiological study based on data for all residents of Australia aged 30-69 years who died between 1986 and 1996 in all States and Territories of Australia. Main outcome measures: Standardised mortality rates from all causes and coronary heart disease as coded by the Australian Bureau of Statistics, and estimated excess deaths in populations living outside capital city statistical divisions. Results: Between 1986 and 1996, mortality from CHD declined by 46% in men and 51% in women, and accounted for 61% of the decline in mortality from all causes in men and 48% in women. More deaths than expected from acute myocardial infarction resulted in mortality rates from CHD up to 30% higher in men and 21% higher in women living outside the capital city statistical divisions, and accounted for an overall estimated excess of 3835 deaths from CHD in men (32% of excess deaths from all causes), and 1385 deaths from CHD in women (27% of excess deaths from all causes) over the 11-year study period. Conclusions: Although there were impressive declines in coronary mortality in all Australian States and Territories from 1986 to 1996, populations living outside capital cities continue to have higher death rates from CHD. These differences in mortality rates indicate a need for further research into factors which may influence mortality rates for CHD in rural and remote areas, and immediate measures to ensure optimal treatment of coronary risk factors and acute coronary events in such populations. Coronary heart disease (CHD) remains the largest single cause of death in Australia.1 Although there has been a steady decline in the death rate associated with CHD over the past 30 years, rates of decline have not been equal throughout Australia.2,3 A study of coronary mortality in Tasmania showed higher rates of mortality outside the capital city region.4 We examined official data for Australian men and women aged 30-69 years between 1986 and 1996 for evidence of differences in rates of death from CHD between capital city and regional populations. Methods The Australian Bureau of Statistics (ABS) collects and disseminates social, demographic and economic statistics for 66 Statistical Divisions based on an Australian Standard Geographical Classification (ASGC).5 The boundaries of capital city statistical divisions are determined by the anticipated development of the city for a period of at least 20 years, and delimit an area that is stable for general statistical purposes. Statistical divisions outside a capital city are relatively homogeneous regions characterised by identifiable social and economic links between the inhabitants and between the economic units within the region, under the unifying influence of one or more major towns or cities. We obtained ABS estimates of the size of the Australian population aged 30-69 years, and its distribution between capital city and other statistical divisions for the years 1986 and 1996. We also obtained ABS data for mortality from all causes, and from CHD, acute myocardial infarction (AMI) and subacute and chronic myocardial ischaemia for men and women aged 30-69 years living within and outside capital city statistical divisions for each year from 1986 to 1996. We excluded deaths at 70 or more years because certification of the cause of death in older people may be unreliable.6 We defined mortality from CHD as deaths with an underlying cause classified under rubrics 410, 411, 413 and 414 of the International classification of diseases, ninth revision (ICD-9-CM),7 with mortality from AMI classified under ICD-9-CM rubric 410, and mortality from subacute and chronic myocardial ischaemia classified under rubrics 411, 413, 414. Statistical methods Annual age-standardised rates for mortality from all causes, CHD, AMI and subacute and chronic myocardial ischaemia were calculated as follows: The number of deaths in each age group (30-39, 40-49, 50-59 and 60-69 years), coded to each cause of death category, were summed. Age-specific rates were calculated and then standardised with weightings obtained from Segi's "world population" (World Health Organization standard population).8 The normal approximation for the distribution was used to calculate 95% confidence intervals. For each State and the Northern Territory, we calculated expected numbers of deaths in each age group for populations living outside capital city statistical divisions by applying age-specific mortality rates from populations living within the capital city statistical division. Differences between the actual (observed) number of deaths and the expected number of deaths were then summed across 10-year age strata to give total expected numbers of deaths. Excess deaths were calculated as the difference between the sum of the observed and the sum of the expected number of deaths for all States and the Northern Territory. The population of the Australian Capital Territory living outside the Canberra Statistical Division was less than 0.1% of the total population of the ACT and was not included in the calculation. Results Population size and distribution Unpublished regional population data from the ABS estimated that, in 1986, there were 7 174 246 Australians aged 30-69 years, 64.4% of whom lived in capital city statistical divisions. The sex distribution in capital cities was 49.9% men and 50.1% women, compared with 51.0% men and 49.0% women outside capital cities. By 1996, the estimated population of Australians aged 30-69 years had increased to 8 793 107, 63.5% of whom lived in capital city statistical divisions. The sex distribution in capital cities was 49.8% men and 50.2% women, compared with 50.7% men and 49.3% women outside capital cities. Trends in mortality rates among men Between 1986 and 1996, mortality from all causes in all 30-69-year-old Australian men declined by 23%; this decline within capital city statistical divisions was 25%, compared with 21% among men living outside capital city statistical divisions (Box 1). Mortality from all causes in populations outside the capital cities remained higher than in capital city populations, with the difference increasing from 12% in 1986 to 18% in 1996. Between 1986 and 1996, mortality from CHD in Australian men aged 30-69 years declined by 46% and accounted for 61% of the decline in all-cause mortality. Mortality among men living within capital city statistical divisions declined by 49%, compared with 41% among men living outside capital city statistical divisions (Box 1). Mortality from CHD in populations outside the capital cities remained higher than in capital city populations, with the difference increasing from 13% in 1986 to 30% in 1996. Mortality from AMI among men living within capital city statistical divisions declined by 62%, compared with 50% among men living outside capital city statistical divisions (Box 1). Mortality from AMI in men living outside the capital cities remained higher than in capital city populations, with the difference increasing from 24% in 1986 to 63% in 1996. Excess mortality outside capital city statistical divisions Box 2 shows that, among men, CHD accounts for 32% of the excess deaths from all causes from 1986 to 1996 occurring outside the capital city statistical divisions. Among those deaths coded as CHD, observed deaths from AMI exceeded expected deaths by 5487. The number of excess deaths from CHD is smaller than that from AMI, as there was a higher rate of death from subacute and chronic myocardial ischaemia in capital city populations. Observed deaths from AMI among men aged 30-39 years living outside capital city statistical divisions exceeded expected deaths by 79%; corresponding figures for the remaining age groups were 72% (40-49 years), 51% (50-59 years), and 25% (60-69 years). Trends in mortality rates among women Between 1986 and 1996, mortality from all causes in all 30-69-year-old Australian women declined by 21%; this decline within capital city statistical divisions was 24%, compared with 18% among women living outside capital city statistical divisions (Box 1). Mortality from all causes in populations outside the capital cities remained higher than in capital city populations, with the difference increasing from 6% in 1986 to 15% in 1996. Between 1986 and 1996, mortality from CHD in Australian women aged 30-69 years declined by 51% and accounted for 48% of the decline in all-cause mortality. Mortality among women living within capital city statistical divisions declined by 54%, compared with 50% among women living outside capital city statistical divisions (Box 1). Mortality from CHD in populations outside the capital cities remained higher than in capital city populations, with the difference increasing from 13% in 1986 to 21% in 1996. Mortality from AMI among women living within capital city statistical divisions declined by 59%, compared with 54% among women living outside capital city statistical divisions (Box 1). Mortality from AMI in women living outside the capital cities remained higher than in capital city populations, with the difference increasing from 24% in 1986 to 38% in 1996. Excess mortality outside capital city statistical divisions Box 2 shows that, among women, CHD accounts for 27% of the excess mortality from all causes occurring outside the capital city statistical divisions. Observed deaths from AMI exceeded expected deaths by 1479. Observed deaths from AMI among women aged 30-39 years living outside capital city statistical divisions exceeded expected deaths by 108%; corresponding figures for the remaining age groups were 75% (40-49 years), 44% (50-59 years), and 20% (60-69 years). Overall mortality Box 3 shows that death rates from CHD outside capital cities are consistently higher than within capital cities in all Australian States and the Northern Territory, the only exception being mortality from CHD among women in the Northern Territory in 1986. Discussion The contribution of reduced CHD mortality to the overall decline in all-cause mortality in Australia from 1986 to 1996 was 61% for men and 48% for women. However, our findings show that CHD mortality rates were higher outside capital cities, and that discrepancies increased from 1986 to 1996 and were largest in younger age groups. It is likely that the differences we found in CHD mortality are real, as they are matched by parallel trends in all-cause mortality rates, and at least two studies have confirmed the validity of deaths coded by the ABS to CHD.9,10 While a study based on 1979 data questioned the validity of subcategories of CHD such as rubric 410 (AMI),11 we found consistently higher death rates from AMI in populations outside capital cities in all Australian States and the Northern Territory (data not shown), despite variations in medical certification requirements between States. The apparent higher rates of mortality in capital city populations from subacute and chronic CHD may be the result of a coding anomaly or of deaths occurring in large population centres after patients were moved there for the management of their subacute or chronic CHD. Our study was limited to documenting the difference in CHD mortality between capital cities and other areas. Clearly, an understanding of the factors associated with higher CHD mortality outside capital cities has implications for prevention and improved treatment of CHD. This would require detailed examination of population characteristics to determine which populations outside capital cities, including subpopulations such as Indigenous people, are most at risk of higher mortality. It is also necessary to consider factors such as differences in socioeconomic status, in risk factors for CHD, and in access to medical care. Previous reports showed that the decline in mortality from CHD in NSW was slower in lower income populations, many of which were in rural or regional areas.12,13 Also, sudden cardiac death in Tasmanian men was found to occur twice as frequently in unemployed men compared with employed men.14 While the association between populations with lower socioeconomic status and higher risk for CHD is recognised, the actual factors that influence this association have not been well delineated. Risk factors for CHD clearly have an influence on mortality. Much of the decline in mortality from CHD in Finland from 1972 to 1992 can be explained by changes in the three main coronary risk factors: serum cholesterol level, blood pressure and smoking.15 In Australia, the National Heart Foundation (NHF) Risk Factor Prevalence Surveys found significant declines between 1980 and 1989 in the prevalence of hypertension and cigarette smoking, but no overall favourable trend in lipid levels.16 However, these surveys are limited to capital cities, and it is not known whether regional areas of Australia have seen the same trends in risk factor prevalence. In 1992, a major risk factor prevalence survey based on the 1989 NHF Risk Factor Prevalence Survey was undertaken in two rural regions of Tasmania. The prevalence of major coronary risk factors was consistent with the high rate of mortality from CHD among men in North-West Tasmania, but did not explain variation in rates of mortality in women across the three regions of Tasmania.17 Differences in mortality from CHD may be the result of differential incidences of CHD or differences in case-fatality rates. A detailed study of sudden cardiac death among previously asymptomatic men found that the higher rate of deaths in the two rural regions of Tasmania occurred mostly among men for whom symptomatic CHD could have been diagnosed, implying a higher case-fatality rate for CHD.14 This finding was supported by higher rates of coronary deaths occurring after hospitalisation in the two rural regions of Tasmania from 1986 to 1989,4 and in Newcastle in 1984.18 A higher case-fatality rate may result from differences in risk of death from factors such as previous infarction, delays in reaching medical care, or differences in medical care.19 While the relative geographic isolation of most populations outside the capital cities may be expected to result in delays in reaching secondary and tertiary medical centres, the findings of the MONICA study did not support changes in time to medical care (including ambulance staff) having a significant effect on deaths before hospitalisation in major population centres.18 A significant decline in case fatality after hospitalisation did, however, make an important contribution to the overall decline in coronary deaths in the MONICA centres of Auckland (New Zealand), Newcastle (Australia) and Perth (Australia) from 1984 to1993. Medical management of acute coronary events has changed substantially over the past 20 years. The use of aspirin, thrombolytic therapy and coronary angioplasty as first-line treatments for AMI has resulted in reductions in mortality of up to 43%.20,21 The use of thrombolytic therapy in the MONICA centres increased from being rare in the early 1980s, to being used in approximately 50% of hospitalised patients with non-fatal definite myocardial infarction or coronary death by the early 1990s.22,23 The benefits of such treatments are dependent on them being given soon after the event,24 and it is not clear whether populations living at any distance from secondary or tertiary medical centres experience delays in access to new treatment methods for symptomatic CHD. In southern Tasmania between 1992 and 1996, 849 doses of streptokinase and tissue plasminogen activator were administered for AMI. No thrombolytic therapy was administered outside the capital city of Hobart (Royal Hobart Hospital Pharmacy Supplies Report), despite 15% of the population of the Southern Region living outside the capital city and having mortality rates approximately 40% higher than the capital city population. In conclusion, although there have been impressive declines in mortality from CHD in all Australian States and Territories over the past 30 years, the 35% of the Australian population living outside the capital cities continue to have higher coronary mortality. Our results indicate the need for increased research into factors which may influence mortality rates for CHD in rural and remote areas. Acknowledgements This study was supported by funding from Roche Products Pty Ltd and the Tasmanian branch of the AMA, and by assistance in-kind from the Hobart City Council and Australian Hospital Care Ltd. We are grateful to Chris Sweeney from the Australian Bureau of Statistics and to the Pharmacy Department of the Royal Hobart Hospital. References Tonkin AM, Bennett S. Cardiovascular disease at the turn of the century. Med J Aust 1999; 170: 408-409. Gibberd RW, Dobson AJ, Florey C du Ve, Leeder SR. Differences and comparative declines in ischaemic heart disease mortality among sub-populations of Australia 1969-1978. Int J Epidemiol 1984; 13: 25-31. Sexton PT, Woodward DR, Gilbert N, Jamrozik K. Interstate differences in trends in coronary mortality and risk factors in Australia. Med J Aust 1990; 152: 531-534. Sexton PT, Jamrozik K, Walsh J, et al. Regional variation in coronary mortality within Tasmania. Med J Aust 1992; 157: 449-451. Australian Bureau of Statistics. Australian Standard Geographical Classification. Canberra: ABS, 1998. Christie D. Mortality from cardiovascular disease. Med J Aust 1974; 1: 390-393. National Coding Centre, Faculty of Health Sciences, University of Sydney. Australian version of the international classification of diseases. 9th revision, clinical modification (ICD-9-CM). 2nd ed. Vol.1: Tabular list of diseases. Sydney: NCC, University of Sydney, July 1996. Doll R. Comparison between registers, age-standardised rates. IARC Sci Publ 1976; 3: 453-459. Martin CA, Hobbs MST, Armstrong BK. Estimation of myocardial infarction mortality from routinely collected data in Western Australia. J Chron Dis 1987; 40: 661-669. Sexton PT, Jamrozik K, Walsh J. Death certification and coding for ischaemic heart disease in Tasmania. Aust N Z J Med 1992; 22: 114-118. Dobson AJ, Gibberd RW, Leeder SR. Death certification and coding for ischaemic heart disease in Australia. Am J Epidemiol 1983; 117: 397-405. Burnley IH. Inequalities in the transition of ischaemic heart disease mortality in New South Wales, Australia. Soc Sci Med 1998; 47: 1209-1222. Taylor R, Chey T, Bauman A, Webster I. Socio-economic, migrant and geographic differentials in coronary heart disease occurrence in New South Wales. Aust N Z J Public Health 1999; 23: 20-26. Sexton PT, Jamrozik K, Walsh J. Sudden unexpected cardiac death among Tasmanian men. Med J Aust 1993; 159: 467-470. Vartiainen E, Puska P, Pekkanen J, et al. Changes in risk factors explain changes in mortality from ischaemic heart disease in Finland. BMJ 1994; 309: 23-27. Bennett SA, Magnus P. Trends in cardiovascular risk factors in Australia. Results from the National Heart Foundation's Risk Factor Prevalence Study, 1980-1989. Med J Aust 1994; 161: 519-527. Thomson A, Rundle S, Singh BB, et al. Regional differences in cardiovascular risk factor prevalence in Tasmania: are they consistent with the increased cardiovascular mortality. Aust N Z J Med 1995; 25: 290-296. Beaglehole R, Stewart AW, Jackson R, et al. Declining rates of coronary heart disease in New Zealand and Australia, 1983-1993. Am J Epidemiol 1997; 145: 707-713. Beaglehole R. Medical management and the decline in mortality from coronary heart disease. BMJ 1986; 292: 33-35. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397-402. Second International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360. Doggen CJM, van der Palen J, Beaglehole R. Trends in medical management of acute myocardial infarction. N Z Med J 1993; 106: 278-281. Dobson AJ, Jamrozik KD, Hobbs MST, et al. Medical care and case fatality from myocardial infarction and coronary death in Newcastle and Perth. Aust N Z J Med 1993; 23: 12-18. Bett JHN. LATE assessment of thrombolytic efficacy with alteplase (rt-PA) six-24 hours after onset of acute myocardial infarction. Aust N Z J Med 1993; 23: 745-748. (Received 23 Sep 1999, accepted 31 Jan 2000) Authors' details The Hobart Private Hospital, Hobart, TAS. Peter T Sexton, PhD, FAFPHM, Director of Medical Services; Tiina-Liisa H Sexton, BCom, CA, Research Assistant. Reprints: Dr P T Sexton, The Hobart Private Hospital, Cnr Argyle and Collins Streets, Hobart, TAS 7000. 1: Comparison of mortality rates between populations aged 30-69 years living within and outside capital cities in Australia Back to text 2: Estimated excess deaths from all causes, CHD and AMI among men and women living outside capital city statistical divisions from 1986 to 1996 Age group (years) 30-3940-4950-5960-69Total Men Mortality from all causes Observed deaths8599126982622760856108380 Expected deaths736310718216195672596425 Excess deaths123619804608413111955 Mortality from CHD (ICD-9-CM 410, 411, 413, 414) Observed deaths682270372391824128865 Expected deaths493209959021653625030 Excess deaths189604 133717053835 Mortality from AMI (ICD-9-CM 410) Observed deaths470197253341328721063 Expected deaths263114435411062815576 Excess deaths207828 179326595487 Women Mortality from all causes Observed deaths38877021138633146756238 Expected deaths32025998119722991851090 Excess deaths6851023189115495148 Mortality from CHD (ICD-9-CM 410, 411, 413, 414) Observed deaths143537 187869379495 Expected deaths91381 150361358110 Excess deaths52156 3758021385 Mortality from AMI (ICD-9-CM 410) Observed deaths102391 140050736966 Expected deaths49223 97242435487 Excess deaths53168 4288301479 CHD=coronary heart disease. AMI=acute myocardial infarction Back to text 3: Mortality within and outside capital city statistical divisions by Australian States and Territories Men Age-standardised mortality rate per 100000 (95% CI) % changeEstimated excess 1986 1996 per yeardeaths from CHD All causesCHDAll causesCHDfrom CHD1986-1996 New South Wales Capital722 (702-741)223 (212-234)511 (496-527)106 (99-113)-4.8 Balance761 (736-786)232 (218-246)601 (581-622)143 (133-153)-3.51506 Victoria Capital658 (638-678)199 (188-210)487 (470-503)97 (90-105)-4.7 Balance755 (722-789)242 (223-261)583 (556-611)131 (118-144)-4.21015 Queensland Capital691 (657-724)226 (207-245)549 (523-575)122 (109-134)-4.2 Balance754 (723-785)227 (210-245)585 (562-609)136 (125-147)-3.6444 South Australia Capital653 (619-687)213 (194-232)528 (499-557)125 (110-139)-3.8 Balance707 (650-764)234 (201-267)633 (583-683)160 (135-186)-2.9291 Western Australia Capital638 (603-673)183 (164-202)498 (471-525)102 (89-114)-4.0 Balance779 (716-841)249 (214-285)594 (546-642)121 (100-143)-4.7203 Tasmania Capital605 (526-684)141 (103-179)595 (520-669)102 (71-133)-2.5 Balance758 (685-831)276 (232-320)619 (558-680)144 (115-174)-4.3243 Northern Territory Capital640 (463-817)115 (46-185)716 (569-863)97 (36-158)-1.4 Balance1443 (1206-1679)233 (138-329)1030 (862-1199)132 (73-191)-3.9133 Australian Capital Territory 598 (521-675)205 (159-251)428 (372-484) 111 (82-140)-4.2 All of Australia Capital679 (668-690)209 (203-215)510 (501-519)107 (103-111)-4.4 Balance763 (747-778)237 (228-245)602 (590-614)139 (133-145)-3.83835 Women Age-standardised mortality rate per 100000 (95% CI) % changeEstimated excess 1986 1996 per yeardeaths from CHD All causesCHDAll causesCHDfrom CHD1986-1996 New South Wales Capital391 (377-405)82 (76-88)284 (273-296)32 (28-36)-5.5 Balance420 (401-439)89 (80-97)335 (319-350)45 (39-51)-4.5564 Victoria Capital360 (346-375)65 (59-72)274 (262-286)31 (27-35)-4.8 Balance361 (338-384)68 (58-77)307 (287-327)35 (28-41)-4.4277 Queensland Capital371 (347-395)67 (57-78)308 (288-328)39 (32-46)-3.8 Balance378 (355-400)75 (65-85)299 (282-316)36 (30-42)-4.7171 South Australia Capital347 (323-371)69 (58-79)285 (264-306)31 (24-38)-5.0 Balance291 (317-400)83 (64-103)339 (301-377)39 (26-52)-4.8143 Western Australia Capital349 (324-374)59 (49-70)275 (255-295)37 (30-45)-3.4 Balance386 (339-433)78 (296-372)334 (57-99)36 (24-49)-4.9105 Tasmania Capital424 (360-488)68 (42-93)365 (308-422)49 (28-70)22.5 Balance421 (367-475)87 (62-111)385 (336-434)54 (36-72)-3.462 Northern Territory Capital434 (271-597)46 (-10-103)392 (261-523)41 (-3-86)-1.0 Balance911 (702-1120)37 (-6-81)762 (593-932)88 (28-148)+12.563 Australian Capital Territory 380 (319-440)56 (32-80)267 (223-311)41 (23-59)-2.4 All of Australia Capital372 (363-380)71 (68-75)284 (278-291)33 (31-36)-4.9 Balance396 (384-407)80 (75-85)326 (317-335)40 (37-44)24.51385 CHD=coronary heart disease. Capital=within capital city statistical divisions. Balance=outside capital city statistical divisions. Back to Text

Peter T Sexton · Tiina-Liisa H Sexton

Editorial Mortality from cardiovascular disease is too high outside capital cities Do we accept this situation or look for ways of changing it? MJA 2000; 172: 360-361 The report by Sexton and Sexton1 in this issue of the Journal updates our knowledge about geographic differences in death rates from cardiovascular disease (CVD) in Australia. Their major finding is that deaths from coronary heart disease (CHD) in 1996 were 30% higher for men and 21% higher for women who live outside our capital cities than for those who live in capital cities. The gap widened over the period of study -- in 1986 the CHD mortality difference (in both men and women) was 13%. The gratifying decline in deaths from CVD over the last number of years has been greater for those who live in capital cities, and this has led to a widening of the geographic gradient in CVD deaths. Of particular concern in the report is that the excess mortality outside capital cities is greater among younger age groups. The demonstration of social and geographic gradients in death rates is not new.2,3 The findings of Sexton and Sexton are disturbing -- what could be the explanation? What can we do about them? There are two reasons for excess CHD deaths -- risk factors among the population and inadequacies in the level of medical care provided. A combination of changes in these factors has been found to be the explanation for the recent decline in CHD deaths seen in Australia.4Sexton and Sexton allude to differences in socioeconomic status between urban and rural areas, which together with higher levels of unemployment outside capital cities may be part of the "explanation" of the higher CHD mortality. Their report does not examine separately death rates in Aboriginal people, and, while these are likely to contribute to the overall picture, Indigenous people constitute too small a proportion of the total population for this to be the whole explanation. Data on risk factor levels are scarce outside capital cities, but some limited data discussed in the report suggest that differences in risk factor levels mirror the excess rural mortality. The strength of the article by Sexton and Sexton is the demonstration of a widening of the mortality gap over time. There have been major changes in the provision of medical care for patients with heart disease between 1986 and 1996, and it seems most appropriate to focus here on the level of healthcare provided in and outside capital cities. The data from Sexton and Sexton do not allow us to distinguish between disease incidence and case fatality, but other data indicate that there are differences in case fatality and in medical care for acute myocardial infarction (AMI) between metropolitan and non-metropolitan hospitals.5,6 There are differences in the types of hospital in and outside capital cities and in the distribution of specialist cardiologists. There is ample evidence that hospital type and size and the speciality of the treating physician are related to the outcome and the practice of evidence-based care for patients with CHD.7-10 A recent report in this Journal found that the evidence-based use of drugs after AMI was lower among doctors in smaller non-metropolitan hospitals in New South Wales.7 It is not beyond credibility to suggest that at least part of the reason for the widening geographic gradient in CHD deaths in Australia is differential levels of care for those with the disease. Rural areas have smaller hospitals and fewer cardiologists (who prefer to have access to investigative facilities, which have become such an important part of their speciality). We must find solutions to the need to practise evidence-based care and prevention throughout the Australian healthcare system, irrespective of access to specialist services and tertiary care facilities. Guidelines and clinical pathways have been promulgated as a response to the demonstration of variations in medical care, and may have an impact on changing patterns of care.11,12 However, the solution to the structural inequalities in the provision of care is likely to be much more complex than the use of these clinical decision aids, especially given the relatively small impact they might be expected to have.12 Do we just accept that people who live outside capital cities in a large country where the population is thinly spread will inevitably have less access to high quality medical care (as they have less access to many other resources such as the arts and retail outlets)? These are fundamental questions about societal expectations. Where is the consumer pressure for change? What is the responsibility of the health professions for the health of the whole of the population, and how is this expressed? A number of these questions were discussed at the recent Federal Government Regional Australia Summit, at which, despite the comment that "There are no easy solutions facing regional Australia", a number of key priorities and proposed strategies were identified.13 For example, two of the key priorities under the health theme are: "Regional, rural and remote communities require improved and expanded access to healthcare services . . ." and "Resource allocation for regional, rural and remote communities must be equitable in terms of health need relative to the urban population." One of the proposed strategies to achieve this latter priority is "A health services plan will be established to set optimal levels of services for communities of different sizes. The Commonwealth Health Department will act as broker for funding to any community which wishes to invoke those benchmarks." Maybe the demonstration of a reduced geographic gradient for CVD deaths could be a future marker of the success of this and other interventions. Richard F Heller Professor of Community Medicine and Clinical Epidemiology Centre for Clinical Epidemiology and Biostatistics Faculty of Medicine and Health Sciences The University of Newcastle, Newcastle, NSW Sexton PT, Sexton T-L H. Excess coronary mortality among Australian men and women living outside the capital city statistical divisions. Med J Aust 2000; 172: 370-374. Taylor R, Chey T, Bauman A, Webster I. Socio-economic, migrant and geographic differentials in coronary heart disease occurrence in New South Wales, Australia. Aust N Z J Public Health 1999; 23: 20-26. Marmot M, Ryff CD, Bumpass LL, et al. Social inequalities in health: next questions and converging evidence. Soc Sci Med 1997; 44: 901-910. Dobson AJ, McElduff P, Heller R, et al. Changing patterns of coronary heart disease in the Hunter Region of New South Wales, Australia. J Clin Epidemiol 1999; 52: 761-771. Huy Dinh Vu, Heller RF, Lim LLY, et al. Hospital mortality after acute myocardial infarction is lower in metropolitan than non-metropolitan regions. J Epidemiol Commun Health. In press. Lim L, O'Connell R, Heller R. Differences in management of heart attack patients between metropolitan and regional hospitals in the Hunter Region of Australia. Aust N Z J Public Health 1999; 23: 61-66. Lim LLY, Heller RF, O'Connell R, D'Este C. Stated and actual management of acute myocardial infarction among different specialties. Med J Aust 2000; 172: 208-212. Chen J, Radford MJ, Wang Y, et al. Do "America's best hospitals" perform better for acute myocardial infarction? N Engl J Med 1999; 340: 286-292. Jollis JG, Delong ER, Peterson ED, et al. Outcome of acute myocardial infarction according to the speciality of the admitting physician. N Engl J Med 1996; 335: 1880-1887. Weitzman S, Cooper L, Chambless L, et al. Gender, racial, and geographic differences in the performance of cardiac diagnostic and therapeutic procedures for hospitalised acute myocardial infarction in four states. Am J Cardiol 1997; 79: 722-726. Kitchiner DJ, Bundred PE. Clinical pathways [editorial]. Med J Aust 1999; 170: 54-55. Gupta L, Ward JE, Hayward RS. Clinical practice guidelines in general practice: a national survey of recall, attitudes and impact. Med J Aust 1997; 166: 69-72. Regional Australia Summit communiquŽ. Presentation of the summit recommendations. <http://www.dotrs.gov.au/regional/summit/communique.htm> (Accessed 23 March 2000). Make a comment

Richard F Heller

Abstract Cardiovascular risk factors are commonly associated with erectile dysfunction and should be identified and treated. Patients with cardiovascular diseases should be assessed and counselled regarding their fitness for sexual activity. The danger of concurrent use of sildenafil and nitrates under any circumstances, regardless of age and sex, must be highlighted at all levels of the community. Sildenafil is absolutely contraindicated in patients receiving treatment with long-acting nitrates for ischaemic heart disease. Patients who need sublingual short-acting nitrates infrequently should not be precluded from taking sildenafil, provided they are aware that sildenafil is not to be taken within 24 h of taking the nitrate. There has been concern about the use of sildenafil (Viagra; Pfizer) for the treatment of erectile dysfunction (ED), particularly with regard to its possible role in the reported deaths and other serious cardiovascular events. Although sildenafil attracted considerable free media publicity in its debut in Australia and ranks as the most publicised new product this decade,1,2 consumer interest has been subdued and partly overshadowed by reports of 130 deaths involving sildenafil users in the United States between late March and mid-November 1998.3 It is therefore important that the association between sildenafil and these deaths be examined critically, so that the nature and the degree of risk may be identified and proper guidelines may evolve for the use of sildenafil. Cardiovascular disease and erectile dysfunction Cardiovascular disease and ED are known to be associated. In the Massachusetts Male Ageing Study,4 moderate or complete ED was 31% more prevalent among people with heart disease than in an age-matched cohort without heart disease. In a study in Perth, WA, the prevalence of complete ED among patients with hypertension, ischaemic heart disease and peripheral vascular disease was 26%, 38% and 57%, respectively, compared with 18.6% for the whole study.5 Reported ED in patients hospitalised for myocardial infarct or coronary artery surgery is of the order of 57%-64%.6,7 Conversely, in patients with severe ED, there is a 16% risk of severe, clinically occult ischaemic heart disease.8 Indeed, a statistically significant correlation has been shown between ED and the number of occluded coronary vessels.9 A significant number of patients requesting treatment for ED will have known or undiagnosed ischaemic heart disease, leading to considerable potential for adverse cardiovascular events. Moreover, many medications used for the treatment of cardiovascular disease may aggravate ED or complicate its treatment.10 Sildenafil and erectile dysfunction Sexual stimulation leads to the release of nitric oxide in the corpus cavernosum and results in an increase of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation and increased blood flow. Sildenafil is a selective inhibitor of cGMP-specific type 5 phosphodiesterase (PDE), the enzyme responsible for the degradation of cGMP in the corpus cavernosum. Thus, it enhances the effects of cGMP and permits an erectile response to be achieved or sustained (Box 1). The relevant pharmacodynamic and pharmacokinetic characteristics of sildenafil are summarised in Box 2.11-13 The efficacy of sildenafil in the treatment of ED has been demonstrated in 21 randomised, double-blind, placebo-controlled trials involving more than 3000 patients aged 19-87 years with ED of various aetiology.11 Sildenafil has been studied in men with ischaemic heart disease and with a wide range of other risk factors.14 A low incidence of serious or clinically significant adverse events, including cardiovascular events, was reported, comparable to that in patients with no known history of cardiovascular disorders. In Phase II-III studies involving 349 placebo patient-years and 693 sildenafil patient-years in randomised studies and 4220 patient-years in open-label studies, the incidence of myocardial infarction was lower in the sildenafil group than in the placebo group, although the difference was not statistically significant. The incidence of adverse events attributable to lowering of blood pressure in patients taking sildenafil was also low and no higher than in those receiving placebo. It was similar in patients taking concomitant antihypertensives and in those not taking these medications.14 There were reports of 26 deaths in about 5000 sildenafil patient-years, including 14 people with myocardial infarction and sudden death. None of the deaths was considered to be treatment related.14 Sildenafil and adverse cardiovascular events The unprecedented hype generated by the launch of sildenafil in the United States was dampened by reports of cardiovascular events, including deaths, allegedly associated with its use. A summary of reports of death among sildenafil users was posted by the Food and Drug Administration (FDA), with the pertinent remark that, in interpreting these reports, consideration should be given to the limitations of spontaneous reporting, such as under-reporting, duplication, marketing and medicolegal factors, incomplete or inaccurate clinical information, and the assumption of a cause-effect relationship.3 An overview of the FDA's updated summary of 130 reports of death between late March and mid-November 1998 is shown in Box 3. Deaths have also been reported in the Netherlands15 and Australia.16 Did sildenafil cause or contribute to the reported deaths? Sexual activity remains a potential trigger for myocardial infarction and sudden death may result from ischaemia or arrhythmia, although the relative and absolute risks are apparently low (Box 4). In the US general population with an age distribution similar to that of sildenafil users, there are about 400 deaths per million per week, and about 150 of these have a cardiovascular cause.29 In Australia, there are about 250 myocardial infarctions (50 fatal) per week affecting men aged 35 to 69 years.30,31 More than 70% of the deceased subjects in the FDA summary had overt or occult cardiovascular disease. Considering the high prevalence of risk factors for sudden cardiac death in users of sildenafil, the reported 130 deaths need to be viewed in the context of patient exposure to about 50 million sildenafil tablets, or more than 6 million prescriptions, during the same period. Pharmacologically, the action of sildenafil as a type 5 PDE inhibitor is highly specific. Potential for disaster seems to lie in the concurrent use of sildenafil and organic nitrates, as sildenafil potentiates the effect of nitrates and may lead to life-threatening hypotension (Box 1). Among the deaths reported in the FDA summary, there were 16-19 sildenafil users who had allegedly used or received glyceryl trinitrate or a nitrate-containing medication. In this subset of individuals, the concurrent use of nitrates would provide the possible causal link between sildenafil and death. Therefore, it is not unlikely that sexual activity in a vulnerable person and adverse drug interaction caused or contributed to the reported deaths. Recommendations Box 5 shows the recommended strategy for treating ED. To minimise adverse consequences, it is important that a patient's fitness for sexual and physical activity be assessed when treatment of ED is considered, and that the patient be appropriately counselled if sexual activity is inadvisable. In general, sexual intercourse should be safe if a patient can perform an activity equal to 5-6 metabolic equivalents (METS), such as climbing 20 stairs in 10-15 seconds without distress.32 Postinfarction patients who reach 5-6 METS on stress testing without ischaemia or arrhythmia can resume their normal sexual activity without risk.33 In one study, patients with a negative exercise test result did not demonstrate ischaemia on Holter monitoring during sexual intercourse.26 The frequent use of short-acting nitrates and ongoing therapy with long-acting nitrates are absolute contraindications to the use of sildenafil. The only option for patients in this situation is to avoid the use of sildenafil. A policy of refraining totally from the use of sildenafil in all patients receiving nitrates in whatever form and regardless of frequency would, of course, quarantine patients from the risk of drug interaction. Nevertheless, patients who have only an infrequent need for short-acting nitrates, such as sublingual glyceryl trinitrate, should not be precluded from the use of sildenafil. However, doctors need to ensure that patients fully understand the implications of the potential interaction of these therapies. Patients whose only exposure to nitrate therapy is infrequent use of sublingual glyceryl trinitrate tablets or spray should be advised that at least 24 hours from the last use of the short-acting nitrates should be allowed to elapse before the use of sildenafil. It is not definitely known when nitrates can be safely administered after a dose of sildenafil. Certainly, patients should be cautioned against the use of any form of nitrates for at least 24 hours after sildenafil. In elderly patients, and in those with hepatic and renal impairment or receiving medications which may inhibit the cytochrome P450 3A4 isoenzyme (eg, erythromycin, fluconazole, fluoxetine, cimetidine), consideration must be given to decreased sildenafil clearance. If a patient should develop angina within 24 hours of taking sildenafil, nitrates should be totally avoided. Doctors should ensure that their patients follow this advice carefully. If necessary, an increase in the dose of alternative anti-anginal agents should be considered. If a patient requires hospital admission, non-nitrate anti-anginal preparations such as ß-blockers or calcium-channel blockers can be used with due regard to the risk of hypotension. If complications should develop from the inadvertent concurrent use of a nitrate, the recommendations of the American College of Cardiology and the American Heart Association34 should be followed. These include resuscitative measures such as fluid infusion and judicious use of intravenous vasopressors to maintain blood pressure, as well as appropriate non-nitrate anti-anginal agents. If adherence to such guidelines is difficult, the alternative is to avoid sildenafil in favour of other therapeutic options for ED. Clinical judgement and discretion must prevail over generalisation, bearing in mind the risk and benefit and the priority of the therapeutic interventions involved. There are no established data on the safety and efficacy of sildenafil in patients with myocardial infarction or life-threatening arrhythmia within the preceding six months; patients with systolic blood pressure < 90 mmHg; or patients with cardiac failure or coronary artery disease causing unstable angina. Caution must be exercised in prescribing sildenafil for these patients and for patients receiving complicated multidrug antihypertensive therapy.34 Where appropriate, monitoring of blood pressure at the initiation of sildenafil therapy would identify patients with a hypotensive response to sildenafil. An appropriate educational program will reduce the risk of drug interaction by alerting pharmacists and doctors to the potential danger. Pharmaceutical companies marketing nitrate-containing medications should specify sildenafil as a contraindication in their product information. Paramedics, nursing staff, patients and the community at large should be instructed on the danger of the concurrent use of sildenafil and nitrates, and of the undesirable practice of sharing medication with relatives and friends (Box 6). It is important that a warning be given to every patient, regardless of sex or age. Women have been known to use sildenafil to heighten sexual arousal and young people may use amyl nitrite inhalation for recreational pursuit. Cardiovascular diseases affect an estimated 2.3 million Australians.35 The risk of angina increases with age, affecting 12.4% of men and 11.7% of women aged 65-69 years.36 These proportions are likely to be greater among patients with ED. A request for treatment of ED provides a window of opportunity to assess the patient for cardiovascular and other risk factors, including diabetes and abnormal lipid profile. Cardiovascular risk factors, if identified, should be vigorously treated according to established guidelines.37,38 The sildenafil controversy continues.39 It has been reported that the FDA continues to believe that sildenafil remains safe.39 However, continuing postmarketing surveillance is essential for sildenafil, as for any recently marketed drug. Disclosure B G A Stuckey has served as a principal investigator in clinical studies of sildenafil. K K Chew and B G A Stuckey have received sponsorship to attend conferences from Pfizer Aust Pty Ltd. P L Thompson serves on the international steering committee of a Pfizer-sponsored clinical trial of lipid lowering in the elderly. K K Chew, B G A Stuckey and P L Thompson have been invited to present papers at Pfizer-sponsored meetings. References Kiely M. Viagra saturates media. Marketing Globe. Marketing 1998; Dec: 58. Jones A. When the thrill has gone. Business Rev Weekly 1999; June 25: 90-95. US Department of Health, Food and Drug Administration. Postmarketing safety of sildenafil citrate (Viagra) and summary of reports of death in Viagra users received from marketing (late March through mid-November 1988). 24 November 1988. Feldman HA, McKinlay JB, Goldstein I, Longcope C. Erectile dysfunction, cardiovascular disease and cardiovascular risk factors: prospective results in a large random sample of Massachusetts men. J Urol 1998; 159 Suppl 5: 91 abstract 347. Chew KK, Earle CM, Stuckey BGA, et al. Erectile dysfunction in general medical practice: prevalence and clinical correlates. Int J Impot Res 2000; 12: 1-5. Wabrek AJ, Burchell RC. Male sexual dysfunction associated with coronary heart disease. Arch Sex Behav 1980; 9: 69-75. Gundle MJ, Reeves BR, Tate S, et al. Psychosocial outcome after aortocoronary artery surgery. Am J Psychiatry 1980; 137: 1591-1594. Anderson M, Nicholson B, Louie E, Mulhall JP. An analysis of vasculogenic erectile dysfunction as a potential predictor of occult cardiac disease. J Urol 1998; 159 Suppl 5: 30 abstract 118. Greenstein A, Chen J, Miller H, et al. Does severity of ischaemic coronary disease correlate with erectile function? Int J Impot Res 1997; 9: 123-126. Slag MF, Morley JE, Elson MK, et al. Impotence in medical clinic outpatients. JAMA 1983; 249: 1736-1740. Morales A, Gingell G, Collins M, et al. Clinical safety of sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res 1998; 10: 69-74. Viagra -- approved product information. Pfizer, 1998. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47-52. Zusman RM, editor. Cardiovascular data on sildenafil citrate. Am J Cardiol 1999; 83(5A). Feenstra J, van Drie-Pierik RJHM, Lacle CF, Stricker BHC. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957-958. Viagra is here! Australian Adverse Drug Reactions Bulletin 1998; 17(4). Hellerstein HK, Friedman EH. Sexual activity and the postcoronary patient. Arch Intern Med 1970; 125: 987-999. Bohlen Y, Held JP, Sanderson MO, Paterson RP. Heart rate, rate-pressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1974; 144: 1745-1748. Willich SN, Klatt S, Arntz HR. Circadian variation and triggers of acute coronary syndromes. Eur Heart J 1998; 19 Suppl C: C12-23. Nalbangtil I, Yigitbasi O, Kiliccioglu B. Sudden death in sexual activity. Am Heart J 1976; 91: 405-406. Ueno M. The so-called coital death. Jpn J Legal Med 1963; 17: 330-340. Renshaw DC, Karstaedt A. Is there (sex) life after coronary bypass? Comp Ther 1988; 14: 61-66. Lecomte D, Fornes P, Nicolas G. Stressful events as a trigger of sudden death: a study of 43 medico-legal autopsy cases. Forensic Sci Int 1996; 79: 1-10. Muller JE, Mittleman MA, Maclure M, et al. Triggering myocardial infarction by sexual activity. JAMA 1996; 275: 1405-1409. Johnston BL, Fletcher GF. Dynamic electrocardiographic recording during sexual activity in recent post-myocardial infarction and revascularization patients. Am Heart J 1979; 98: 736-741. Drory Y, Shapira I, Fisman EZ, Pines A. Myocardial ischaemia during sexual activity in patients with coronary artery disease. Am J Cardiol 1995; 75: 835-837. Kavanagh T, Shephard RJ. Sexual activity after myocardial infarction CMAJ 1977; 116: 1250-1253. Paolillo V, Marra S, Spadaccini F, Angelino PF. Dynamic electrocardiographic recording during sexual activity in recent post-myocardial infarction and revascularization patients [letter]. Am Heart J 1980; 100: 763. Health United States. 1998. Hyattsville, Maryland: US National Center for Health Statistics, 1998. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases, Australian facts. Canberra: AIHW and the Heart Foundation of Australia, 1999. (Cardiovascular Disease Series No. 10. AIHW Cat. No. CVD 7.) Australian Bureau of Statistics. Causes of death, Australia. Canberra: ABS, 1997. (Cat No. 3303.0.) Cardiac rehabilitation: sex after a heart attack. In: Zaret BL, Moser M, Cohen LS, editors. Yale University School of Medicine Heart Book. New York: Hearst Books, 1992; 351. Tardif GS. Sexual activity after a myocardial infarction. Arch Phys Med Rehabil 1989; 70: 763-766. Summary statement of the American College of Cardiology and the American Heart Association on the use of sildenafil (Viagra) in patients at clinical risk from cardiovascular effects. 10 August 1998. <http://www.americanheart.org/ Whats_News/AHA_Science_Advisories/viagra.html>. Accessed 18 February 2000. Fact sheet for prevention of myocardial infarction. National Heart Foundation of Australia. Curr Ther 1999; 39: 52. Fact sheet for angina. National Heart Foundation of Australia. Curr Ther 1999; 39: 63. Grundy SM, Balady GJ, Criqui MH, et al. Guide to primary prevention of cardiovascular diseases. A statement for healthcare professionals from the Task Force on Risk Reduction. Circulation 1997; 95: 2329-2331. Heart Foundation of Australia. Guide for the use of lipid lowering drugs in adults. Canberra: Heart Foundation of Australia, 1999. Available at <http://www. heartfoundation.com.au/include/defaultStory.asp?OwnerUID=200&Content Type=tblcategory>. Mitka M. Some men who take Viagra die -- why? [news]. JAMA 2000; 283(5). <http://jama.ama-assn.org/issues/v283n5/full/jmn0202-2.html>. Accessed 18 February 2000. (Received 8 Oct 1999, accepted 14 Feb 2000) Authors' details Keogh Institute for Medical Research, Perth, WA. K Kim Chew, FRCP(Edin), FRCP(Glas), Senior Clinical Fellow; Bronwyn G A Stuckey, MB BS, FRACP, Medical Director, and Consultant Endocrinologist, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, WA. University of Western Australia, Perth, WA. Peter L Thompson, FRACP, FACP, Clinical Professor of Medicine, University of Western Australia, and Consultant Cardiologist, Sir Charles Gairdner Hospital, Perth, WA. Reprints will not be available from the authors. Correspondence: Dr B G A Stuckey, Keogh Institute for Medical Research, 3rd Floor A Block, Queen Elizabeth II Medical Centre, 2 Verdun Street, Nedlands, WA 6009. rmriATwt.com.au 2: Pharmacodynamic and pharmacokinetic characteristics of sildenafil11-13 Sildenafil is about 4000-fold more selective for type 5 phosphodiesterase (PDE5) than for PDE3, which is involved in cardiac contractility. In healthy volunteers, sildenafil produced a modest decrease in blood pressure (up to 8.4 mmHg systolic and 5.5 mmHg diastolic), but no consistent orthostatic effects and no clinically relevant electrocardiographic changes. In patients receiving medications containing nitrates, the hypotensive effects of sildenafil can be severe. In a US study with isosorbide mononitrate 20 mg twice daily, 50 mg sildenafil produced maximal blood pressure reductions of 40.9 mmHg systolic sitting and 51.6 mmHg systolic standing, and 25.8 mmHg diastolic sitting and 29.3 mmHg diastolic standing, about one hour after dosing and lasting up to 6 h. Similar haemodynamic interaction occurred for about two hours after a dose of 500 µg sublingual glyceryl trinitrate (maximum reductions: systolic, 36.0 mmHg sitting; diastolic, 20.5 mmHg sitting). Sildenafil has a half-life of about 4 h. After an oral dose of 100 mg, the plasma level peaks at about 440 ng/mL within 30-120 min, and drops to about 2 ng/mL at 24 h. Sildenafil is predominantly metabolised in the liver by the cytochrome P450 3A4 system, and 18% of the dose is excreted in the urine. Increased plasma levels may result from concomitant use of a cytochrome P450 3A4 inhibitor (eg, erythromycin, fluconazole, fluoxetine, cimetidine) or reduced clearance in elderly persons (>65 years) and in those with significant hepatic and renal impairment (creatine clearance <30 mL/min). 3: US Food and Drug Administration summary of reports of death in sildenafil users Number of deaths reported130Number with cause not mentioned or unknown48Number from homicide or drowning2Number from stroke3Number from cardiovascular events Definite or suspected myocardial infarction Cardiac arrest Cardiac symptoms Coronary artery disease77 41 27 6 3Use of nitrates Took or were administered a nitrate medication Found with nitrate in their possession16 3Time of death after use of sildenafil Not stated or unknown Within 4-5 hours of using sildenafil (includes 27 during or immediately after sexual intercourse) Later the same day Next day Two days later Three to seven days later61 44 6 8 5 4Cardiovascular risk factors One or more risk factors No identified risk factors, but severe coronary artery disease found at autopsy No history of cardiac disease or risk factors No risk factors and no sexual activity Not specified 90 3 12 2 23 4: Sexual activity and adverse cardiovascular events Sexual activity, like any other physical effort, increases cardiac work and myocardial oxygen demand.17 Heart rate and blood pressure rise to an energy expenditure of 2.0-5.4 metabolic equivalents.18 Sexual activity may trigger an adverse cardiovascular event.19,20 Coital death has been reported to account for 0.6% of sudden deaths,21 although it is said to be rare in a stable sexual relationship.22 In a study of 43 cases, sudden death was found to occur primarily in patients with severe heart disease, especially coronary heart disease, and in only three cases was sexual activity involved.23 In another study, 9% of patients reported having had sexual activity in the 24 hours, and 3% in the two hours, preceding myocardial infarction. The relative risk of myocardial infarction occurring in the two hours after sexual activity was estimated to be 2.5, and was not increased in patients with a history of previous angina pectoris or myocardial infarction. The absolute risk increase was low, at one chance in a million for a healthy individual.24 Electrocardiographic abnormalities during sexual activity have been reported in 12 of 24 patients with recent myocardial infarction or revascularisation.25 In another study, 31% of men with ischaemic heart disease had ischaemia on Holter monitoring during sexual intercourse, although only 7% were symptomatic.26 However, the frequency of angina pectoris and ventricular premature beats is less during sexual intercourse than during standard laboratory exercise, and sexual relations are thought to carry no special risk for the average postinfarction patient.27 Sexual activity in the early posthospital phase of myocardial infarction is not a stronger stimulus than other activities for cardiac electrical instability.28 Anxious sexual preoccupation, frustration and avoidance may actually be greater risk factors than coitus or coital alternatives.22

Peter L Thompson

Editorial Mood disturbances and coronary heart disease: progress in the past decade Psychological factors are increasingly being identified as important contributors to the onset and course of coronary heart disease MJA 2000; 172: 151-152 Psychological conditions, such as life event stress, mood disturbance and personality disorders, are believed to be important risk factors for coronary heart disease (CHD).1-3 Building on the work of the past decade, growing evidence is emerging that mood disturbances can contribute substantially to CHD. This work has studied the effect of a range of emotional conditions, including hostility and anger, but we will focus here on anxiety and depressed mood. Anxiety Studies of patients with pre-existing CHD show that anxiety, independently of conventional risk factors, can be predictive of recurrent acute CHD events.4 Moreover, prospective studies of anxiety in normal populations show that there is an association between anxiety assessed at enlistment and subsequent CHD mortality over many years, even when conventional risk factors are controlled for -- the relative risks are significant, being of the order of 5-6 for sudden death and 2-3 for fatal acute myocardial infarction (AMI).5 Impressive data also come from prospective studies of panic disorder, which show that CHD mortality risk may be doubled in people with the disorder.6,7 There has been strong supportive psychophysiological evidence -- for example, in patients with pre-existing CHD undergoing ventriculography and exposed to trivial experimental stressful tasks, a significant but transient reduction (of up to 50%) in coronary muscle perfusion can occur.2,8 At the other end of the evidence hierarchy are the clinical case reports of patients with panic disorder, found to be free of CHD at angiography, who have had an acute AMI or ongoing angina following panic attacks.9 It has furthermore been shown that patients with panic disorder, while lacking any demonstrable peripheral elevation in serum catecholamine levels, nonetheless have significant release of adrenaline from the coronary sinus during panic attacks.10 This may in turn adversely affect coronary perfusion, cardiac rhythm, shear forces on atheromatous plaques, and platelet function.11 States of severe emotional arousal can also affect underlying pathophysiological risk factors for CHD, including platelet function and haemostasis.12,13 Longer-term effects of anxiety on cardiovascular pathophysiology are also possible; it has been shown that subjects with an exaggerated blood pressure response to mental stress may experience more rapid progression of carotid atherosclerosis.14 Depressed mood Depressed mood is emerging as an important risk factor for CHD. Depressed mood in CHD patients is associated with increased mortality.15 The increased risk is not trivial (relative risk > 3), being of the same order as other risk factors such as prior AMI and impaired left ventricular function after infarction. Even in long-term studies of normal CHD-free populations, depression at enlistment doubles the risk of subsequent acute coronary events16 and increases mortality risk.17 States resembling depression, such as "vital exhaustion" (characterised by fatigue, irritability and demoralisation),18 have been shown to be associated with acute myocardial events in normal populations even when conventional risk factors are controlled. Unlike the more acute effects of anxiety, the effects of depression are not immediate. Indeed, in one prospective study, mortality rates in women with depression did not begin to increase until after 16 months of follow-up.19 Thus, depression may well have a prolonged mode of action on CHD risk. One study found that one component of depression (ie, hopelessness) was associated with more rapid progression of atherosclerosis.20 The CHD risk of a person with chronic depression or dysphoric mood, either as an induced state or an enduring trait of "depressive" personality, needs further study. Personality Recently the "type D ('distressed') personality" has been described by Denollet et al as a result of finding significant differences in CHD outcome in those with certain personality traits. The type D personality is identified by two components: the continual experience of negative emotions, including depression, and the inhibition of social expression of these emotions. In a sample of patients undergoing cardiac rehabilitation, deaths from cardiac causes were increased fourfold in those with type D personality even after controlling for conventional risk factors.21 This suggests that type D personality (whether as a biological construct of temperament or a constellation of habitual behaviours) is a risk factor at least equivalent in importance to the other, "conventional" coronary heart disease prognostic factors. Implications It is possible that the association between mood and CHD risk is not causal, but that the two are linked by some common underlying genetic factor, perhaps associated with vascular disease in general. Weighted against this interpretation are the experimental findings showing the effect of emotions on cardiovascular pathophysiology. To explore the possibility of covariance, prospective aetiological and interventional studies are necessary to examine both mood state (which is episodic) and the personality-based predisposition (trait) to depression. Intervention studies are now in progress to assess whether antidepressants may reduce CHD events in those with depression following AMI.22 In the meantime, in patients with pre-existing CHD or those at increased risk of CHD, the identification and treatment of mood disorders, including anxiety and depression, is important for improving quality of life and for reducing the risk of CHD events and mortality. Christopher C Tennant Professor, Department of Academic Psychiatry Loyola McLean Lilly Psychiatry Research Training Fellow Department of Academic Psychiatry Royal North Shore Hospital, St Leonards, NSW tennantATmed.usyd.edu.au Hemingway H, Marmot M. Evidence-based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. BMJ 1999; 318: 1460-1467. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 1999; 99: 2192-2217. Tennant CC, Palmer KJ, Langeluddecke PM, et al. Life event stress and myocardial reinfarction: a prospective study. Eur Heart J 1994; 15: 472-478. Moser DK, Dracup K. Is anxiety early after myocardial infarction associated with subsequent ischemic and arrhythmic events? Psychosom Med 1996; 58: 395-401. Kawachi I, Gollditz G, Ascherio A, et al. Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 1994; 89: 1992-1997. Coryell W, Noyes R, House JD. Mortality among outpatients with anxiety disorder. Am J Psychiatry 1986; 143: 508-510. Weissman MM, Markowitz JS, Ouellette R, et al. Panic disorder and cardiovascular/cerebrovascular problems: results from a community survey. Am J Psychiatry 1990; 147: 1504-1508. Tennant C. Experimental stress and cardiac function. J Psychosom Res 1996; 40(6): 569-583. Mansour VM, Wilkinson DJ, Jennings GL, et al. Panic disorder: coronary spasm as a basis for cardiac risk? Med J Aust 1998; 168: 390-392. Wilkinson DJ, Thompson JM, Lambert GW, et al. Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks. Arch Gen Psychiatry 1998; 55: 511-520. Deedwania PC. Hemodynamic changes as triggers of cardiovascular events. Cardiol Clin 1996; 14: 229-238. Grignani G, Pacchiarini L, Zucchella M, et al. Effect of mental stress on platelet function in normal subjects and in patients with coronary artery disease. Haemostasis 1992; 22: 138-146. Malkoff SB, Muldoon MF, Zeigler ZR, Manuck SB. Blood platelet responsivity to acute mental stress. Psychosom Med 1993; 55: 477-482. Kamarck TW, Everson SA, Kaplan GA, et al. Exaggerated blood pressure responses during mental stress are associated with enhanced carotid atherosclerosis in middle-aged Finnish men: findings from the Kuopio Ischaemic Heart Disease Study. Circulation 1997; 96: 3842-3848. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995; 91: 999-1005. Ford DE, Mead LA, Chang PP, et al. Depression is a risk factor for coronary artery diease in men: the precursors study. Arch Intern Med 1998; 158: 1422-1426. Simonsick EM, Wallace RB, Blazer DG, Berkman LF. Depressive symptomatology and hypertension-associated morbidity and mortality in older adults. Psychosom Med 1995; 57: 427-435. Appels A, Otten F. Exhaustion as precursor of cardiac death. Br J Clin Psychol 1992; 31: 351-356. Whooley MA, Browner WS. Association between depressive symptoms and mortality in older women. Arch Intern Med 1998; 158: 2129-2135. Everson SA, Kaplan GA, Goldberg DE, et al. Hopelessness and 4-year progression of carotid atherosclerosis. The Kuopio Ischaemic Heart Disease Risk Factor Study. Arterioscler Thromb Vasc Biol 1997; 17: 1490-1495. Denollet J, Stanislas US, Stroobant N, et al. Personality as independent predictor of long-term mortality in patients with coronary heart disease. Lancet 1996; 347: 417-421. Shapiro PA, Lesperance F, Frasure-Smith N, et al. An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant Heart Attack Trial. Am Heart J 1999; 137: 1100-1106. Make a comment

Christopher C Tennant · Loyola McLean

Editorial Defibrillation for out-of-hospital cardiac arrest Strengthening that most important link in the "chain of survival" MJA 2000; 172: 53-54 Cardiac arrest outside hospital is a common mode of unexpected death in our society. The arrest is usually caused by coronary artery disease, and indeed may be its first manifestation, occurring in apparently fit and well individuals. The causative arrhythmia is usually ventricular fibrillation, but by the time help arrives and the rhythm is recorded it has often degenerated into asystole. In this issue of the Journal, Meyer et al1 present a detailed medical perspective of this problem, and outline the steps we need to take to improve the survival rate for victims of out-of-hospital cardiac arrest, particularly the "chain of survival" -- the critical links in the resuscitation process. When a cardiac arrest is witnessed, the first priority is defibrillation, but in most situations cardiopulmonary resuscitation (CPR) needs be undertaken before defibrillation. The spectacular success of implantable defibrillators in terminating lethal arrhythmias2 in patients known to be at extreme risk of ventricular fibrillation raised the possibility that the same sensing technology and defibrillator waveforms might be incorporated into an external defibrillator, without the need for rhythm interpretation by a medical or paramedical attendant. Such devices were introduced over 10 years ago, and have been widely implemented, with results for successful defibrillation by junior ambulance officers that were as good as those of paramedics.3 By 1990, the New South Wales Ambulance Service had introduced semiautomatic defibrillators into all its frontline ambulances (ie, those not used for routine transport) to complement the care given by paramedics with manual defibrillators. Similar systems have since been initiated in other Australian States. By 1991, the concept of public access defibrillation (PAD) was re-emerging. This idea was first conceived by the pioneer of prehospital coronary care, Frank Pantridge of Belfast,4 who developed a small but primitive defibrillator in the late 1960s which could be installed next to every fire extinguisher and used in the same way, simply and easily, and by whoever was closest. Pantridge asked the question "Is property more important than life?". With the re-emergence of this concept within the American Heart Association, the aim was to have semiautomatic defibrillators so widely available, and sufficient members of the public trained, that a person who suffered a cardiac arrest in a public place might have the benefit of a defibrillator before the arrival of an ambulance and when the chance of a successful outcome may be well over, rather than well under, 50%.5 Semiautomatic defibrillators are now deployed in what may seem to be the most unlikely places,5 and Australia has played a leading role. They were first installed in the QANTAS International fleet and in Australian airports during 1991.6 The long-term survival rate for people treated on the ground or in the air by QANTAS International staff is 32%,7 now exceeded by the seven of 14 (50%) for people treated by American Airlines staff over the past 18 months.8 Defibrillators are deployed widely in Chicago's O'Hare Airport and are available for public access. Deployment of public access defibrillators in airports is becoming commonplace, and Sydney's international and domestic terminals will be equipped with a system similar to Chicago's within months. Installation in airliners is becoming the industry standard throughout the world,8 with programs completed or under way for most major international and domestic airlines (including QANTAS and Ansett Domestic). Use in airports and airliners has followed awareness of the fact that deaths from cardiac arrest in the air are far more common than deaths from aircraft crashes,7,8 while deaths in terminals of people undergoing unaccustomed exercise are more common than at other locations9 (except at sporting venues, where deaths in older spectators are common). Survival rates of 70% have been reported from the Melbourne Cricket Ground10 and in Las Vegas casinos:11 in both situations remote monitoring of crowd activity enables quick recognition, which, together with appropriate placement of personnel and devices, ensures a prompt response. Deployment of defibrillators in police cars, complementing the ambulance service in the environs of the Mayo Clinic, has increased community survival after cardiac arrest in Rochester, Minnesota, to near 50%.12 St John Ambulance, as the leading teacher of community resuscitation and first aid in Australia, has endorsed training in defibrillation with CPR, and is embarking on an ambitious program, through its training and operational arms, to make public access defibrillation widely available throughout the nation. Such a program must mesh with the existing professional ambulance service, and complement this by strengthening that most important earliest link in the "chain of survival" -- the prompt reversal of ventricular fibrillation by whoever can do so first, and fastest. In strife-torn Belfast, Pantridge's idea lapsed because no system was available at the time for automatic recognition of ventricular defibrillation, so the device had to be used in the manual mode, and could have been used as a weapon. The introduction of safe semiautomatic defibrillators which will only operate in the presence of ventricular fibrillation has changed this situation. A satisfactory answer can now be given to Pantridge's question. As peace emerges in Ulster, the concept proposed by Pantridge and Geddes4 has taken firm root throughout the whole world. Michael F O'Rourke Professor of Medicine University of New South Wales and St Vincent's Hospital and Clinic, Sydney, NSW Meyer ADMcR, Cameron PA, Smith KL, McNeil JJ. Out-of-hospital cardiac arrest. Med J Aust 2000; 172: 73-76. Moss AJ, Hall WJ, Cannon DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996; 335: 1933-1940. O'Rourke MF, Hall J. Pre-hospital cardiac arrest in New South Wales (1992). Aust N Z J Med 1994; 24: 619. Geddes JS, editor. The management of the acute coronary attack: the J Frank Pantridge Festschrift. London: Academic Press, 1986. Nichol G, Hallstrom AP, Kerber R, et al. American Heart Association Report on the Second Public Access Defibrillation Conference, April 17-19, 1997. Circulation 1998; 97: 1309-1314. Donaldson E, O'Rourke MF. Defibrillators on QANTAS aircraft. Med J Aust 1992; 156: 293. O'Rourke MF, Donaldson E, Geddes JS. An airline cardiac arrest program. Circulation 1997; 96: 2849-2853. Crewdson J. Code blue: survival in the sky. Chicago Tribune Aug 1, 1999: C1-C3. Becker L, Eisenberg M, Fahrenbruch C, Cobb L. Public locations of cardiac arrest: implication for public access defibrillation. Circulation 1998; 97: 2106-2109. Wassertheil J, Keane G, Fisher N, Leditschke JF. Cardiac arrest outcomes at the Melbourne Cricket Ground and Shrine of Remembrance using a tiered response strategy -- a forerunner to Public Access Defibrillation. Resuscitation 2000. In press. Valenzuela TD, Bjerke HS, Clark LL, et al. Rapid defibrillation by non-traditional responders. The Casino project. Acad Emerg Med 1998; 5: 414-415. White RD, Hankins DG, Bugliosi TF. Seven years' experience with early defibrillation by police and paramedics in an emergency medical services system. Resuscitation 1998; 30: 145-151. Make a comment

Michael F O'Rourke