Letters

Timothy J McCulloch Anaesthetist, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050. tmccullATusyd.edu.au To the Editor: Chilov and colleagues have presented an updated set of guidelines for management of hip fracture, which included the statement “regional anaesthesia is recommended for most patients”.1 The evidence for this recommendation was graded as Level I (National Health and Medical Research Council) and was supported by a single reference, namely a systematic review from the Cochrane Database by Parker et al.2 Parker et al performed a meta-analysis of the published trials examining the effect of regional versus general anaesthesia on a variety of outcomes after surgery for hip fracture. A possible difference in 1-month mortality was found in favour of regional anaesthesia, but this difference was borderline using one statistical model (relative risk, 0.7; 95% CI, 0.5–1.0) and non-significant using another model. There was no significant difference in mortality at 3 months or 1 year, and no significant difference in a variety of other outcomes. Appropriately, the authors concluded that “both regional and general anaesthesia produce comparable results and therefore anaesthetists should choose which technique is most appropriate for each individual patient”.2 One of the many difficulties in interpreting meta-analyses of regional anaesthesia is that most of the published trials were performed some decades ago. For example, one study that contributed a large proportion of the data within the Cochrane meta-analysis was conducted between 1980 and 1982, and patients were explicitly excluded if they were receiving low-dose anticoagulation therapy.3 The relevance of such trials to patients receiving general anaesthesia today is highly questionable, given the improvements in general anaesthetic drugs and techniques and the importance now placed on routine thromboprophylaxis. There is a wide range of opinion within the specialty of anaesthesia regarding the place of major regional blockade, with little outcome-based evidence to support any particular advantage of these techniques. Although medical practitioners can benefit greatly from the efforts of reviewers to develop guidelines based on the best available evidence, care must be taken to ensure that recommendations do not go beyond what is supported by available data. Particular care needs to be taken when recommendations are made for areas of practice outside the reviewers’ expertise. The authors of these guidelines might consider withdrawing their recommendation regarding choice of anaesthesia.

Timothy J McCulloch

Michael N Chilov,* Ian D Cameron,† Lynette M March‡ * Intern, Concord Hospital [corresponding author], 50 Mi Mi Street, Oatley, NSW 2223; † Chair, Rehabilitation Medicine, University of Sydney; and Director, Aged Care and Rehabilitation Services, Northern Sydney Area Health Services, Rehabilitation Studies Unit, Ryde, NSW; ‡ Senior Staff Specialist in Rheumatology and Clinical Epidemiology, Department of Rheumatology, Royal North Shore Hospital, St Leonards, NSW. mchilovATgmp.usyd.edu.au In reply: We thank McCulloch for his comments regarding the use of regional anaesthesia in the surgical management of hip fracture. He makes the point that surgical and anaesthetic techniques have improved and implies that the advantage seen for regional anaesthesia in published studies may no longer be present. Given that controversy still exists, we would recommend that further randomised controlled trials be conducted. However, for the following reasons, we stand by our recommendation that the available evidence supports the use of regional anaesthesia for most patients with this condition. Our current recommendation is unchanged from the earlier version of the guideline (published in the Journal in 1999),1 and is also consistent with at least one other published guideline.2 A number of the concerns raised by McCulloch were addressed in the response to a letter by another correspondent after the publication of the original guidelines.3 While we acknowledge that the review by Parker et al4 only found the reduction in mortality at 1 month to be of borderline significance, when our review team reassessed the original articles using the Cochrane Collaboration protocol we reached a summary odds ratio for mortality of 0.68 (95% CI, 0.49–0.96). With time and further studies we expect that this estimate of effect will become more precise as the power of the meta-analysis is increased. This view is supported by a systematic review of all randomised studies comparing regional anaesthesia with general anaesthesia across surgical specialties. The study of Rodgers et al found a statistically significant reduction in mortality (odds ratio, 0.70; 95% CI, 0.54–0.90) when regional anaesthesia was compared with general anaesthesia.5 This overall point estimate is very similar to that of Parker et al in their meta-analysis of patients with hip fracture. Although lack of power meant that statistical significance did not exist within individual surgical specialties, there was, in fact, little difference in the effect across surgical groups, with no significant heterogeneity between studies. Serious complications of regional anaesthesia (eg, spinal haematoma) are extremely rare, as shown in the recent PEP study in Australia and New Zealand that reported no cases in 4603 patients undergoing regional blockade.6 This should be compared with the number needed to treat with regional anaesthesia to prevent one death of 38, according to the data of Parker et al.4 There is no doubt that our recommendation needs to be considered in the context of individual patient characteristics and, while the recommendation may not apply to all patients with hip fracture, we feel that the available evidence supports the use of regional anaesthesia.

Michael N Chilov · Ian D Cameron · Lynette M March

Alan Rodger Medical Director, and Professor of Radiology Oncology, Beatson Oncology Centre, Western Infirmary, Dumbarton Road, Glasgow, G11 6NT, UK. alan.rodgerATnorthglasgow.scot.nhs.uk To the Editor: I strongly support the editorial comments and recommendations of McNeil et al1 on public funding of clinical trials. Having worked in the Australian healthcare system for 11 years, and having returned to a changed National Health Service in Scotland a few months ago, I can vouch for the benefits that accrue from adequate funding for clinical trials. While McNeil and colleagues focus on large-scale trials, their comments apply equally to smaller trials. Certainly, in oncology, several trials organisations in Australia have struggled for years to continue conducting trials in spite of inadequate government funding. The ANZ Breast Cancer Trials Group and the Trans Tasman Radiation Oncology Group are but two organisations with which I am familiar. In addition to precarious funding, I believe the consequences in the past 2 years of upheaval in the insurance industry have placed all such groups on an uncertain and untenable footing. Clinical trials must be ethical, scientific and well managed. Clinicians entering patients into trials need support from essential data managers and clinical nurse specialists. Governments encourage and, in fact, demand evidence-based medicine. The only effective way to produce the evidence is to conduct clinical trials. That costs money. In Victoria, cancer trial management was supported by about $800 000 per annum in grants from the Cancer Council Victoria. Those funds provided start-up assistance to institutions new to clinical trials and supported the others that could not rely on pharmaceutical company largesse. However, only part of that money was state government funded and then only for rural and regional centres or for breast cancer. The diagnosis-related-group-based casemix funding of Victorian hospitals included a notional element for research. That sop was lost in budget deficits. In Scotland, where health matters are totally devolved to the Scottish Parliament, the latter’s Scottish Executive Health Department has very recently enhanced funding for cancer care. This includes £500 000 (A$1.25 million) annually to support clinical research in cancer. Each of the three cancer networks has a guaranteed share of that sum to resource clinical trials in all the associated health boards and cancer units. This is in addition to the excellent clinical trials units in the main cancer centres, often funded by the charity Cancer Research UK and industry. There is also a national system of considering and approving clinical research in cancer. Such approval places obligations on health boards to support such trials. Lastly, accreditation of cancer centres can depend on clinical trial participation. The evidence that this (still imperfect) system has an effect is seen in trial entry at our oncology centre, where 11% of patients are already entered into trials. The new funding should see that increase. Government needs to put its money where its mouth is: evidence needs resourcing. The alternative is to rely on charity or on industry (whose eye is more often on marketing than science).

Alan Rodger

Paul Walker Paediatric Otolaryngologist, John Hunter Children’s Hospital, PO Box 293, New Lambton, NSW 2305; and Conjoint Associate Professor, Disciplines of Surgery and Paediatrics, University of Newcastle. walkerpATtpgi.com.au To the Editor: The study by Paradise et al on tympanostomy tubes for persistent otitis media,1 which was expertly reviewed by Morris and Leach in the Journal recently,2 has since been updated.3 The findings of both studies from Pittsburgh should only be applied with caution in Australia. Indications for inserting ventilating tubes (VTs) can be divided into three: bilateral hearing loss of more than 25–30 dB continuously for 3 months after failed non-operative management; structural damage to the tympanic membrane (TM) which may lead to irreversible hearing loss or cholesteatoma; and a miscellany which includes under-lying sensorineural hearing loss or learning difficulties or similar conditions with deterioration associated with bilateral middle ear effusion (MEE), and recurrent middle ear infections with use of VTs as an alternative to antibiotic prophylaxis, among others. The conclusion of the more recent article by Paradise et al3 — that there was no difference in expressive or receptive speech or cognition between children in whom VTs were inserted early or late — is valuable, but may not readily be extended to Australian practice. Although 6350 children were enrolled, only 397 were actually randomly allocated into the early or late treatment groups. Thus, the numbers are not large. Of more concern is that only 18% of those analysed had bilateral continuous MEE (40 in the early and 32 in the late treatment group), with the remaining 82% having unilateral (continuous or discontinuous) or bilateral discontinuous MEE. Only the 18% with bilateral continuous MEE would ordinarily be candidates for VTs in Australia, as Paradise et al underline the fact that intermittent and/or unilateral MEE is not associated with speech and language difficulties in the absence of other handicaps to learning. An abnormal hearing test result was identified by the study as a 15 dB loss. This could well fall in the normal range for the Australian Hearing Service for children wearing headphones, and a minimum threshold of 25-30 dB should typically be required for considering VTs in Australia. As Morris and Leach2 pointed out for the earlier study,1 the later study also excludes children “not otherwise healthy”,3 and the results cannot be generalised to such children, or to those with moderate rather than mild hearing loss. Pointing to studies such as that of Paradise et al can be very helpful in reassuring parents who want VTs for their child with unilateral or intermittent hearing loss that not having VTs does not place the child’s speech and language development at risk.

Paul Walker

Stacey L Emmett,* Adam J O’Brien,† Joseph E Ibrahim† * Research Officer, † Consultant Physician, Clinical Liaison Service, Victorian Institute of Forensic Medicine and the State Coroner’s Office, 57-83 Kavanagh St, Southbank, VIC 3006. staceyeATvifm.org To the Editor: Root-cause analysis is an established, retrospective, structured investigative technique1 that was first introduced into wide clinical practice in public hospitals in Victoria in 2001.2 It is usually reserved for investigating infrequent and significant adverse events and explores the nature and causes of organisational systems failures.1 It is important for all healthcare professionals to understand this technique, as it is used increasingly by healthcare organisations. Cooper and Blamey’s Lesson from Practice described the outcome of an investigation using root-cause analysis of an occupational exposure to HIV from a needlestick injury.3 We commend the analyses that identified multiple failures of the system for reporting and responding to occupational exposures to hazardous material. The practice changes that ensued at Southern Health demonstrate the value of root-cause analysis. However, more information and analysis is required about the mistaken use of the stored serum samples. As the authors explain, the initial information was that the source patient tested negative for HIV antibodies. Some time later, it was discovered that the specimen tested was not from the source patient but from a patient of the same surname in the same ward. This caused a 3-day delay between the initial test and the Infectious Diseases Unit being notified that the source patient had twice tested positive for HIV antibodies. We contend this is an important and common systems failure that usually makes headlines of the form “Wrong site, wrong procedure, wrong person surgery”. The Joint Commission on Accreditation of Healthcare Organisations developed a universal protocol with the intention of highlighting the causative systems failures and minimising the frequency of recurrences of wrong-site surgery.4 The information given by Cooper and Blamey does not clearly explain why (ie, the root cause) the incorrect specimen was tested initially. The pathology department’s review identified the presence of unacceptable “informal norms” in the practice of blood collection and labelling. The suggested remedy that “all serum should be collected with strict adherence to blood collection and labelling protocols” is unlikely to prevent a recurrence. Exhortation to do better rarely solves the underlying problem. It is therefore important to understand why health professionals violate procedures and protocols.5 The experiences of Cooper and Blamey demonstrate that some of the limitations and benefits of root-cause analysis depend on the depth of the investigation. The early and unquestioning acceptance that strict adherence to an existing protocol will prevent another “wrong person” error is not convincing. This contrasts with the well-conducted inquiry and subsequent management of occupational exposure to needlestick injuries.

Stacey L Emmett · Adam J O’Brien · Joseph E Ibrahim

Elizabeth E Cooper,* Stephen L Blamey† * Sterilisation and Infection Control Coordinator, Southern Health Infection Control and Epidemiology, Southern Health, Locked Bag 29, Clayton, VIC 3168; † Head, Department of GastrointestinaI Surgery, Monash Medical Centre, Melbourne, VIC. elizabeth.cooperATsouthernhealth.org.au In reply: Emmett and colleagues request more information and analysis about the mistaken use of stored serum samples. The pathology staff member correctly labelled the specimen of the patient being bled but did not follow the protocol in identifying that the patient was the same as on the request slip. It had not been highlighted that there were two patients with the same surname (but different first names) in the ward, and blood was collected from one patient with a request slip labelled for another. At specimen reception, the protocols were again not followed, as the staff did not check that the minimum identifiers on the specimen label and request form matched. It is recognised that violations of procedures are not root causes and are not directly manageable. The cause of the procedural violation must be managed.1 The collection and labelling of blood protocols were reviewed after this incident and found to be appropriate. The root-cause analysis identified that the protocols were not followed and that unacceptable “informal norms” had become practice in the collection and labelling of specimens. Staff training was examined and revised to ensure that staff were aware of the content of the protocols and that they followed them accordingly. All staff members were counselled about the importance of following correct procedures and the consequences of not doing so. Up to 1000 specimens are received at specimen reception each weekday. New “front end processing” technology is to be introduced at the end of 2003. This electronically scans the specimen and request slip to ensure details match. In the interim, in recognition that mislabelling will occur, all specimens relating to occupational exposures are collected at the time of the incident. Previously available results and serum stored in the laboratory are not relied on.

Elizabeth E Cooper · Stephen L Blamey

Nicola Magnavita Researcher, Italian Study Group on Hazardous Workers and Institute of Occupational Medicine, Catholic University School of Medicine, Largo Gemelli 8, Rome, 00168, Italy. magnavitaATrm.unicatt.it To the Editor: The article by Charles and colleagues1 is an interesting contribution to the development of Australian protocols for healthcare workers infected with hepatitis C virus (HCV). To date, most European countries have no national policy for HCV-infected healthcare workers, and existing guidelines are advisory in nature and poorly enforced. A panel of European and American experts recently failed to reach consensus on management of HCV-infected healthcare workers who perform exposure-prone procedures, and concluded that screening for HCV infection and restricting infected healthcare workers is not justified, based on current published data.2 Today, the effectiveness of guidelines relies solely on self-assessment of HCV status from healthcare workers. However, collaboration of healthcare workers might be problematic if management criteria are not defined, and workers’ rights are not guaranteed. Issues such as practice restriction, disclosure of serological status to patients, privacy and discrimination need to be resolved. Given the risk of HCV transmission from healthcare workers to patients is not clear, the burden of uncertainty rests entirely with healthcare workers. Because of the fear of discrimination, needlestick injuries may be under-reported, and infected workers may not seek diagnosis and treatment because they have greater legal protection if they can honestly say that they did not know their serological status.3 Moreover, the largely asymptomatic nature of HCV infection may leave healthcare workers unaware of their infective status. The results of Charles and colleagues suggest up to tenfold underreporting of occupational injuries with blood exposure in Australian healthcare workers.1 With this number of unreported exposures, there may be two or three new cases of HCV infection in healthcare workers in metropolitan hospitals in Melbourne each year — a figure similar to the prevalence of occupational HCV infection from notified injuries. Paradoxically, the prevalence of HCV infection in healthcare workers and the transmission risk for patients cannot be assessed without compulsory testing of healthcare workers, but without risk assessment there is no reason for this compulsory testing. Overcoming this Catch-22 with well-targeted epidemiological studies may help create broad consensus about policies for HCV-infected workers.

Nicola Magnavita

Patrick G P Charles,* M Lindsay Grayson,† Peter W Angus,‡ Joseph J Sasadeusz§ * Registrar, Department of Infectious Diseases, † Director, Infectious Diseases and Clinical Epidemiology, ‡ Director, Gastroenterology and Hepatology, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, VIC 3084; § Director, and Infectious Diseases Physician, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VIC. patrick.charlesATmh.org.au In reply: Magnavita correctly points out the need for a national policy on the management of healthcare workers who are either infected with or occupationally exposed to hepatitis C virus (HCV). Compulsory testing of healthcare workers is neither practical, logical nor fair in the current Australian healthcare environment. Firstly, most healthcare institutions do not currently have adequate staff health systems in place to ensure that staff are appropriately vaccinated against readily preventable diseases, such as hepatitis B, measles and varicella, let alone to test all staff for a disease such as hepatitis C, for which there is no vaccine. Secondly, awareness about important issues, such as healthcare worker transmission-risk assessment is embryonic (at best) in most institutions. The risk of HCV transmission from infected healthcare workers to their patients is generally considered to be extremely low, but probably depends on a number of factors, including the nature of the patient’s procedure and the healthcare worker’s injury and level of viraemia at the time. Simplistic legal opinions about such matters rarely help. Finally, we agree that the rights of healthcare workers are often neglected in this era of litigation-driven medicine. If these rights are not considered, and infected or exposed healthcare workers are simply excluded from all types of work without any appropriate risk assessment or compensation, then compliance with any form of postinjury testing is unlikely. However, rather than ignoring this important workplace issue, as we believe many Australian institutions currently do, a logical assessment of potential transmission risk is possible that is both fair to the patient and the infected worker. Stratification of healthcare workers according to their level of HCV viraemia and whether they are involved in exposure-prone procedures is a logical start — this we have attempted in our proposed guidelines.1 Some healthcare workers may avoid being tested so that they can have the protection of not knowing their serological status.2 However, recent studies suggesting the efficacy of early treatment of acute HCV infection3 mean that it will actually be in healthcare workers’ interest to know if they have recently acquired HCV infection — as long as they are treated in a manner that protects their health and workplace rights, while also protecting the rights of their patients.

Patrick G P Charles · M Lindsay Grayson · Peter W Angus · Joseph J Sasadeusz

Caroline M de Costa Obstetrician and Gynaecologist, Cairns Base Hospital, Cairns, QLD 4870. carolinedecAThotkey.net.au To the Editor: As a “grand multip” myself, I turned with interest to Humphrey’s recently published study of grand multiparity and pregnancy risk at Cairns Base Hospital.1 However, I cannot support his conclusions. Throughout the period of the study, most grand multiparous women giving birth at this hospital were actively managed in the third stage of labour with a regimen designed to prevent postpartum haemorrhage (intravenous ergometrine/oxytocin). Women of lesser parity were also given preventive therapy, but generally in lower doses and less consistently. This is a major confounding factor not addressed in Humphrey’s study. Clearly, an unknown, but probably significant, number of haemorrhages were prevented by this treatment. Given that 9.2% of grand multiparous women still had a postpartum haemorrhage, any prospective randomised controlled trial that allowed some of these women not to have active management of the third stage would be unethical. Numerous other studies have shown an association between grand multiparity and postpartum haemorrhage. 2-4 These include the study of Babinszki and colleagues, which limited study subjects to upper-class, private patients and thereby eliminated many confounding variables.4 Humphrey’s study does not report the severity of the postpartum haemorrhages that did occur; even a small number of life-threatening haemorrhages could justify continuing very active preventive measures in grand multiparous women. The incidences of anaemia and previous postpartum haemorrhage, not recorded in the study, would also be of interest; both are independent reasons to actively manage the third stage in women of any parity, and there are good reasons to believe that both may be more common in grand multiparous women. Humphrey also states that grand multiparous women did not have higher perinatal mortality rates or poorer maternal outcomes than women of lower parity. However, whenever possible throughout the period of the study, grand multiparous women were identified on booking into antenatal care and treated by senior obstetricians. Many had conditions such as diabetes, hypertension, anaemia and heart disease managed carefully to ensure as good a pregnancy outcome as possible. This focused obstetric care could well have counteracted any natural tendency of grand multiparous women towards poorer outcomes, and thus it is not possible to draw any conclusions about perinatal results from the data provided. What is clear from these data is that grand multiparous women in far north Queensland are often economically and socially disadvantaged compared with women of lower parity. This is a common finding in almost all studies of grand multiparity. 2,3,5 We should remember that these women are taking home a new baby to conditions that may already be quite compromised. They deserve the best obstetric care we can offer them, and we should be very cautious when reviewing protocols that we do not increase risks to these women or their babies.

Caroline M de Costa

Michael D Humphrey Director, Obstetrics and Gynaecology, Women's and Children's Health Service, King Edward Memorial Hospital, PO Box 134, Subiaco, WA 6904. Michael. HumphreyAThealth.wa.gov.au In reply: I thank de Costa for her interest in the debate about excessive medicalisation of normal childbirth in women with significant parity. The obstetric protocol manual of Cairns Base Hospital did not, at any time, discriminate in the details of management of the third stage of labour between grand multiparous and non-grand multiparous women. The statistical analysis in my report shows that, once confounding factors are accounted for, grand multiparous women who labour spontaneously are twice as likely as their less parous counterparts to have a spontaneous vaginal birth, with no statistically greater risk of a postpartum haemorrhage requiring transfusion.1 The purpose of multivariate analysis is to remove, as far as possible, the influences of the confounding factors that de Costa’s appraisal relies on. The recommendation from my study is not that grand multiparous women be ignored, but that, if labour occurs spontaneously at the end of an uncomplicated pregnancy, they be treated no differently to their less parous sisters in terms of venous cannulation and blood cross-matching. I am on record as strongly recommending sensible, routine oxytocin-based management of the third stage of labour in all pregnancies.2 In the end, the question is whether or not evidence wins out over an individual’s historically influenced clinical beliefs.

Michael D Humphrey

Neil H Cradick General Practitioner, PO Box 1127, Buderim, QLD 4556. cradwhitAToptusnet.com.au To the Editor: On opening the MJA Focus document “Prevention of cardiovascular disease: an evidence-based clinical aid”,1 I expected to find useful and contemporary guidelines for general practice. However, I was surprised to read two of the recommendations — for the use of antihypertensive and antiplatelet drugs in “low risk” patients (those without risk-associated clinical conditions or end-organ damage). The document recommends drug treatment only if systolic blood pressure is > 180 mmHg or diastolic blood pressure is > 100 mmHg in people under 60 years, or systolic blood pressure is > 160 mmHg in people over 60 years. While Fulcher et al1 volunteered that this was at odds with clinical practice, they supported the recommendations by stating that they were in accordance with published guidelines. The data for these conservative hypertension parameters were published nearly 10 years ago,2 or derived from textbooks,3 and are at odds with the 1999 WHO/ISH guidelines,4 and even more at odds with the excellent Joint National Committee (JNC 7) report.5 The latter publication recommends, after lifestyle recommendations, drug treatment for a blood pressure of 140–159/90–99 mmHg for those without end-organ damage. Furthermore, the focus document recommends primary prevention with aspirin in those with a calculated annual cardiovascular event risk > 3%. Hayden et al6 suggest antiplatelet treatment should be offered to those with a 5-year cardiovascular event risk > 3%, which equates to a > 0.6% annual risk. The benefit to harm ratio needs to be explained to the individual, and therapy should only be initiated once blood pressure is controlled. As an interested general practitioner and user of evidence-based guidelines, I usually check the funding of publications, and, with the heavy emphasis on the use of ACE inhibitors (in particular ramipril) and statins (which are produced by Aventis Pharma), it is difficult to rely on the evidence as presented. I would hope that independent bodies such as the National Prescribing Service or Australian Prescriber could take the pharmaceutical lead and produce desktop references with a more unbiased opinion on the latest collection of evidence that is shaking us up in primary care medicine. I would again refer readers to the excellent hypertension guidelines mentioned above4,5 (in particular the JNC 7 reference card available on the Internet at www.nhlbi.nih.gov/guidelines/hypertension/jnc7card.htm), and caution them to remain wary of easy-reference desktop items funded by pharmaceutical companies.

Neil H Cradick

Gregory R Fulcher,* John V Amerena,† Greg W Conner‡ * Director, Department of Diabetes, Endocrinology and Metabolic Medicine, Level 3, Main Block, Royal North Shore Hospital, St Leonards, NSW 2065; † Cardiologist, Department of Clinical and BioMedical Sciences, University of Melbourne, Melbourne, VIC; ‡ Vascular Physician, Cardiovascular Diagnostic Services, Sydney, NSW. gfulcherATmed.usyd.edu.au In reply: We thank Cradick for his critical review of our publication.1 His interesting points illustrate some of the reasons we were keen to publish this work. Firstly, the average practitioner is confused about which guidelines (both national and international) to follow. Cradick refers to the JNC 7 report and WHO/ISH guidelines (the committee is familiar with these), but which to follow? The committee decided a priori that Australian national guidelines, if they existed, would be referenced in preference to overseas ones. We mentioned that current Australian hypertension guidelines should be revised, and that clinical practice was probably at odds with these recommendations. Secondly, guidelines quickly become dated. Cradick cites the recommendation of Hayden et al that aspirin should be introduced if the annual risk of a cardiovascular event is > 0.6%.2 The latest Australian guidelines3 recommending a > 1% annual risk as the treatment threshold were published just after we received Cradick’s letter. The Hayden article is thus (for some patients) at odds with current local recommendations. Consistent with our approach, we will include the Australian recommendations in the first update of our document (July 2004). Cradick’s comments imply bias in the presentation of the data; yet he fails to substantiate this. Neither the clinical trials quoted (nearly all of which are funded by the pharmaceutical industry) nor the conclusions or inferences drawn have been challenged. He refers to the “heavy” emphasis on the use of ACE inhibitors and statins, implying that this is inappropriate. We would argue that, given the strength of the evidence, this emphasis is appropriate, and reflects current specialist practice in tertiary centres. Careful reading of the National Prescribing Service publications will show that “heavy” reference is made to the 4S,4 LIPID,5 CARE,6 and WOSCOPS7 studies (for example, NPS News 20 February 20028), as well as to the prescribing information for Lipitor (Pfizer), Pravachol (Bristol-Myers Squibb) and Zocor (Merck Sharp & Dohme). We must caution against “throwing the baby out with the bathwater”. The HPS, CARE, LIPID, WOSCOPS, HOPE, PROGRESS, 4S, CURE, and CREDO studies represent substantial and widely acclaimed clinical trials that have had a positive impact on clinical care. They have all been funded by the pharmaceutical industry. Finally, about 130 GPs in clinical practice had some input in compiling and formatting this document. The document was tested before publication in over 30 000 patients, and was peer reviewed by several clinicians. It is a pity that Cradick was not a participant in any of these processes.

Gregory R Fulcher · John V Amerena · Greg W Conner

Michael Thomsen,* Luis Vitetta,† Mathias Schmidt,‡ Avni Sali§ * Research Associate, † Director of Research, § Head, Graduate School of Integrative Medicine, Swinburne University, 9 Frederick Street, Hawthorne, VIC 3122; ‡ Head of Toxicology, Society of Nutritional Medicine and Dietetics, Harsewinkel, Germany. lvitettaATmedicine.swin.edu.au To the Editor: Gow and colleagues recently attributed fulminant hepatic failure in an Australian patient to an over-the-counter herbal product containing kava (Piper methysticum) that is extensively used in the community.1 We are not convinced that kava caused this patient’s liver failure. The hepatotoxicity could have been due to other unidentified contaminants of the herbal preparation or to chromium (from the mineral supplements also taken by the patient). We tested a sample of the product Kava 1800 Plus (Eagle Pharmaceuticals, Batch No. 10711) by thin layer chromatography (TLC) and high pressure liquid chromatography (HPLC) methods, and assessed it against defined standards. Kavalactones were identified and quantified by normal-phase HPLC. Kava was positively identified, with a content of about 47 mg of kavalactones per tablet (the product label specifies 60 mg per tablet). However, flavonoids from Scutellaria lateriflora, analysed by reverse-phase HPLC, could not be found. Passiflora incarnata, analysed by TLC, was also not found, with none of the typical flavonoid bands being detectable. The absence of two ingredients listed on the product label, P. incarnata and S. lateriflora, raises a new concern that there may be batch variations, as well as the possibility of unknown adulterants or contaminants being present. The possibilities of contaminants and batch variation were not excluded in the case report by Gow and colleagues.1 The Therapeutic Goods Administration established that Kava 1800 Plus did not contain common germander (Teucrium chaemaedrys), a known adulterant for S. lateriflora. However, Teucrium species are known to have hepatotoxic effects and there are about 100 species, any one of which could have been a contaminant. Gow et al refer to 68 international case reports of suspected hepatotoxicity with the use of kava.1 An independent analysis of these 68 cases concluded that only two were probable kava-associated hepatotoxicities.2 An incidence calculation from these case reports indicates that hepatotoxicity from kava occurs in 0.008 cases per million daily doses,2 which represents an extremely low risk of adverse reactions associated with kava. Recently, a study on the potential hepatotoxicity of kava found that the aqueous extract of kava does not affect results of liver function tests in rats. Extracts were administered in daily dosages of 200 or 500 mg of active kavalactones per kilogram of bodyweight for 2 or 4 weeks. Sera were assayed for four enzymes that are markers of liver toxicity, and liver homogenates were assayed for malondialdehyde formation, which indicates changes in lipid peroxidation. Kava did not elevate malondialdehyde or the enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase or lactate dehydrogenase. In fact, in certain instances, these enzymes were significantly reduced, suggesting a lack of toxic effect of kava on the liver.3 TLC analyses have shown that there is no qualitative difference between aqueous, acetone or ethanol extracts of kava.4 We propose, given that patients can consume other over-the-counter products such as chromium (shown to have hepatotoxicity at high concentrations),5 that all products consumed by patients must be evaluated before causality can be attributed to a particular herb. Reports of case records associated with hepatic failure due to kava require proper verification and documentation of all the findings.

Michael Thomsen · Luis Vitetta · Mathias Schmidt · Avni Sali

Paul J Gow,* Nathan J Connelly,† Richard L Hill,‡ Peter Crowley,§ Peter W Angus¶ * Gastroenterologist, † Gastroenterology Registrar, ¶ Director, Department of Gastroenterology and Liver Transplantation, § Pathologist, Department of Anatomical Pathology, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, VIC 3084; ‡ Medical Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Canberra. paul.gowATarmc.org.au In reply: Thomsen et al raise several points regarding our recent report of a death following ingestion of a preparation containing kava.1 The first is that the results of their analysis of the herbal preparation differ from those of the Therapeutic Goods Administration (TGA). The TGA found Passiflora incarnata in the tablets, whereas Thomsen and colleagues did not. The explanation for this lies in the fact that different batches of the product were analysed by the two laboratories. The analysis we reported relates to batch 13861, which was the source of the patient’s tablets. Thomsen and colleagues have analysed material from a different batch that may have contained different components. Thomsen et al also raise the possibility that Teucrium, a known adulterant of Scutellaria, may have been present in the preparation. With respect to this issue, the TGA tested for both T. chamaedrys and T. canadensis and found none present. They also tested for the presence of the chemicals teucreoside and verbascoside, both of which are found in many Teucrium species. Neither was present. The raw materials used to make the tablets were also analysed, and no evidence of Teucrium substitution or contamination could be found. The next point raised is whether the association between kava use and hepatotoxicity is causal, and they quote an analysis published in the journal Phytomedicine, in which the authors claimed that kava was the probable cause in only two of 68 reviewed cases. In marked contrast, the Journal of Hepatology, in July 2003, published an analysis of 36 cases of hepatitis associated with the use of kava.2 The review concluded that kava was the certain or probable cause of the hepatitis in 24 of the 36 cases. Worryingly, eight of these patients required liver transplantation. Thomsen and colleagues then point to a lack of evidence of hepatotoxicity in studies in rats administered kavalactones.3 We believe it is inappropriate and misleading to suggest that a study of this kind could rule out the possibility that kava preparations cause life-threatening but uncommon idiosyncratic hepatotoxic reactions in humans. Finally, Thomsen et al wonder whether the patient’s illness may have been due to chromium toxicity. However, the illness was not suggestive of chromium poisoning.4 There is no reason to believe that chromium was present at other than normal background levels.

Paul J Gow · Nathan J Connelly · Richard L Hill · Peter Crowley · Peter W Angus

Colin L Crawford Retired physician, 23 Grafton Road, London, W3 6PB, UK clcraw13AThotmail.com To the Editor: The Australian Drug Evaluation Committee (ADEC) has recommended that thalidomide be approved for the management of erythema nodosum leprosum. This recommendation has now been accepted by the Therapeutic Goods Administration. Was ADEC unaware that the World Health Organization no longer recommends thalidomide in the management of this complication of lepromatous leprosy?1,2

Colin L Crawford

Martin H N Tattersall Chairman, Australian Drug Evaluation Committee; and Professor of Cancer Medicine, Blackburn Building D06, University of Sydney, Sydney, NSW 2006 mtattATmed.usyd.edu.au In reply: When it considered thalidomide for registration for management of erythema nodosum leprosum (ENL) and another indication (myeloma), the Australian Drug Evaluation Committee (ADEC) was not aware that the World Health Organization (WHO) does not recommend the drug for this indication. ADEC bases its recommendations on review of the scientific and clinical evidence submitted concerning the efficacy and safety of products submitted for registration. In the case of thalidomide in the management of ENL, ADEC reviewed the results of several randomised studies, together with additional published reports. Data from the US Public Health Service analysing the entire experience of thalidomide use in ENL in the United States from 1978 to 1994 were also reviewed. The committee concluded that the efficacy of thalidomide in acute ENL is beyond dispute. Moreover, thalidomide was also shown to be useful in patients with ENL already treated with corticosteroids and dapsone. ADEC discussed the side-effect profile of thalidomide in the ENL studies and concluded that skin rashes, sometimes with eosinophilia, were somewhat more common than in the myeloma studies that were also reviewed. In regard to safety concerns relating to thalidomide’s teratogenicity, the committee was informed of the sponsor’s proposed risk management program, which is based on mandatory registration of prescribing doctors, patients and dispensing pharmacists. This program is based on an effective program in the US, where the Food and Drug Administration has registered thalidomide for treatment of ENL. ADEC felt that the risk–benefit ratio favoured registration for ENL (and myeloma). However, the committee resolved that a boxed warning should be included stating: Thalidomide has caused severe birth defects when taken during pregnancy. Thalidomide should never be used by women who are pregnant or who could become pregnant whilst taking the drug, or could become pregnant within four weeks after stopping the drug. Even a single dose can cause severe birth defects. I have reviewed the WHO documents referred to by Crawford,1,2 and consulted Medline. I have also had access to a review article in press in the Lancet.3 I believe the evidence indicates that thalidomide is superior to steroids in controlling ENL. Britton and Lockwood state that thalidomide is the drug of choice for men with ENL;3 however, they comment that using thalidomide in women with ENL is a difficult decision for a woman and her doctor. The WHO documents emphasise that any benefit from thalidomide must be balanced against its known toxicity, and conclude that experience has shown that it is virtually impossible to develop and implement a foolproof surveillance mechanism to combat thalidomide toxicity. ADEC concludes that thalidomide is an effective and useful drug in the management of ENL, and that the risk management program which is to be established in Australia, together with the inclusion of a boxed warning, will ensure that the risk–benefit profile of thalidomide use in ENL is favourable.

Martin H N Tattersall

Lynne M Roberts,* Lucy Bowyer,† Caroline S Homer,‡ Mark A Brown§ * Research Midwife [corresponding author], † Senior Lecturer in Obstetrics (University of New South Wales), ‡ Midwifery Consultant, Department of Women’s and Children’s Health, St George Hospital, Research Building, St George Hospital, Kensington Street, Kogarah, Sydney, NSW 2217; § Professor of Medicine (University of New South Wales), Department of Renal Medicine, St George Hospital. RobertslyATsesahs.nsw.gov.au To the Editor: The obstacles presented by Human Research Ethics Committees (HRECs) have caused a significant delay in commencing a valuable research project. We are currently conducting a multicentre study investigating the outcomes of hypertensive pregnancies in a cohort of 1620 women. It is a retrospective review of medical records and does not entail any participation of the women. Ethics approval was sought and gained from the New South Wales Health Department and one other NSW area health service (AHS) involved in the study. The bulk of the medical records (85%) are held by this AHS and a smaller proportion by eight other AHSs in NSW. Despite these prior approvals, the process of gaining ethics approval from the eight AHSs was fraught with obstacles at every stage. After 8 months’ work, we have received approval from the HREC of each of the AHSs. Our experience has revealed many inconsistencies in the requirements of the HRECs in the different AHSs, as summarised in the Box 1. These inconsistencies highlight discordances with the guidelines to support researchers and HRECs drawn up by the National Health and Medical Research Council (NHMRC). The NHMRC’s National Statement on Ethical Conduct in Research Involving Humans1 clearly outlines that, once approval has been gained from one HREC, other sites should accept that approval. Unfortunately, it seems that the HRECs involved in giving approval for our study did not follow the guidelines relating to multicentre projects. Other researchers have reported similar problems. 2-4 Breen and Hacker2 suggest that HRECs are slow to adopt a simplified review process because this interferes with traditional practices of each committee making its own assessment. It is indisputable that ethics considerations are a vital component when undertaking human research. It is also crucial to have a reliable and trustworthy process that evaluates research proposals in order to protect participants from physical and psychological harm. However, it has taken the research midwife (who is on a 1-year non-renewable grant) 8 months to secure ethical approval at all sites. This process is cumbersome and counterintuitive to the principles and guidelines for multicentre research in this country. 1: Summary, by area health service (AHS, coded S to Z), of different requirements for gaining ethics approval for a multicentre study Area health service S T U V W X Y Z No. of pages of application form 19 20 19 20 12 23 2 11 No. of copies of form required 1 1 17 15 20 16 1 14 No. of hospitals in AHS covered by approval 2 2 4 1 3 5 3 5 Approval covered private hospitals in AHS also na na Yes No No na No na No. of contacts made (phone/letter/email) to gain approval 20 15 20 15 20 30 10 20 Time taken to gain approval 3 months 5 months 4.5 months 8 weeks 6 weeks 6 weeks 1 week 3 weeks Special requests during approval process A F A, B, C, E A A, D A G, H Approved after first submission Yes No No Yes Yes Yes Yes Yes na = not applicable. A = Asked for local researcher to be a contact person for the study. B = Charged a $33 fee to submit application. C = Requested scientific protocol with references. D = Requested budget form. E = Reviewed by scientific advisory committee before human research ethics committee (HREC). F = Requested consent and subject information forms. G = University HREC’s approval as well as approval of area health service HREC required. H = Final approval required from chief executive officer of major hospital in that AHS.

Lynne M Roberts · Lucy Bowyer · Caroline S Homer · Mark A Brown

Gautam Ramnath,* Peter Bampton† * Gastroenterology Registrar, † Head of Endoscopy, Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042. peter.bamptonATflinders.edu.au To the Editor: Reflux oesophagitis is an increasingly common medical condition, and up to 10% of all patients with reflux oesophagitis have associated columnar-lined oesophagus, or Barrett’s oesophagus (Box 1).1 This is associated with an increased risk of adenocarcinoma in Australian data of 1 in 176 patient-years.2 Current surveillance guidelines for Barrett’s oesophagus recommend second-yearly endoscopy with quadrantic biopsies at 2–3 cm,3,4 although recent reviews have suggested that the time interval can be extended.1 No prospective study has demonstrated that screening for Barrett’s oesophagus improves survival in the screened population. All the evidence is based on retrospective reviews. If, however, screening is to be of benefit, then adequate tissue sampling is required, otherwise the screening test provides false reassurance and is a poor use of endoscopy resources. We retrospectively audited the endoscopies performed for Barrett’s oesophagus (with intestinal metaplasia) surveillance at our institution over 5 years (1996–2001). In this period, 253 endoscopies were performed as surveillance procedures for Barrett’s oesophagus. We reviewed the endoscopy and histopathology reports to determine whether an adequate number of biopsies had been taken. We found that quadrantic biopsies (defined as four biopsies per 2 cm or less) at every 2–3 cm were performed in 27 of 72 (38%) short-segment, 27 of 150 (25%) long-segment (3–10 cm), and 1 of 13 (8%) extensive (> 10 cm) Barrett’s oesophagus. An acceptable number of biopsies were taken from 40% of patients. The number of biopsies taken per centimetre of Barrett’s oesophagus was inversely proportional to the length of Barrett’s oesophagus. The median interval between surveillance procedures was 12 months. In most surveillance procedures (137/217; 63%) the endoscopy was performed following medical review in the outpatient department rather than because of planned call-back, although in only a few cases did it appear to be due to alarm symptoms such as dysphagia or weight loss. There was little consistency in recommendations among the medical staff. Only one cancer was identified through surveillance in this period, with another presenting in a patient previously on the call-back system who had been lost to follow-up. Three high-grade dysplasias were found. Our retrospective audit revealed that the endoscopists were not following biopsy guidelines, and revealed significant variances in practice. Previously, we found a similar picture with post-polypectomy surveillance; with re-education and development of a prospective review of all cases, we have been able to greatly improve this aspect of practice.5 We were surprised at the result of our audit, and invite other endoscopy units to perform a similar audit of their own practice. It has encouraged us to develop a process similar to the one we have adopted to improve post-polypectomy surveillance. This should improve our practice and enable more efficient utilisation of the endoscopy facility. 1: Barrett’s oesophagus

Gautam Ramnath · Peter Bampton

Mark R Nelson NHMRC Research Fellow, Department of Epidemiology and Preventive Medicine, Monash University, Commercial Road, Prahran, VIC 3181. mark.nelsonATmed.monash.edu.au To the Editor: The lessons from the introduction of COX-2-selective non-steroidal anti-inflammatory drugs (NSAIDs), related by Kerr et al,1 have a corollary in the introduction of angiotensin-II-receptor antagonists 2 years previously. Both cases involved common conditions (osteoarthritis and hypertension), with extensive prescribing of newly developed and marketed agents, which blocked an enzyme further down the cascade of reactions to avoid adverse outcomes — the gastrointestinal upset and bleeding associated with non-selective NSAIDs, and the cough and angioedema caused by angiotensin-converting enzyme inhibitors. In both conditions, off-patent, low-cost alternative drug therapies were available — paracetamol and acetylsalicylic acid, and thiazide diuretics and β-blockers, respectively. My quantitative investigation of general practitioners’ perceptions of newer versus older antihypertensive agents suggested that they thought newer agents were more efficacious, and were safer in the short term and long term, but were more expensive.2 These beliefs were held despite the lack of long-term safety data. Younger doctors were more likely to hold these beliefs. It is possible that the experience of using older medications permitted older doctors to maintain a healthy scepticism towards the marketing claims of medical representatives. It may be interesting for Kerr and colleagues to look at the demographics of GPs in the General Practice Research Network to see if these findings hold true for this cohort.

Mark R Nelson

Ian D Coombes,* Danielle A Stowasser,† Charles A Mitchell,‡ Paul Varghese§ * Leader, Adverse Drug Event Prevention Project, Queensland Health Medication Management Services, ‡ Associate Professor of Medicine, § Director of Geriatric Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, QLD 4102; †Manager, Queensland Health Medication Management Services, Royal Brisbane Hospital, Brisbane, QLD. Ian_coombesAThealth.qld.gov.au To the Editor: We would like to add our perspective to the discussion on computerised prescribing.1 Electronic prescribing with appropriate decision support is recognised by the Medication Safety Taskforce of the Australian Council for Safety and Quality in Health Care as a key initiative to prevent patient harm.2 Such systems reduce the opportunity for prescribing errors and improve patient safety.3 The widely espoused benefit of the clarity and legibility associated with electronic prescribing appears to have led many to assume that electronic prescribing is an essential component of medication safety systems whether or not it includes a decision support system. In fact, electronic prescribing without decision support has been associated with an increase in the incidence of error4 and inappropriate use of medications.1 A computer-generated discharge summary was developed at a tertiary referral teaching hospital in Brisbane. With this system, a discharge prescription was generated using information entered from the database by the medical officer. As part of standard practice, a pharmacist reviews all discharge prescriptions and compares them with the inpatient medication chart, discussing any apparent errors with the medical officer. We conducted an audit of 200 consecutive medical discharge prescriptions (100 generated by computer and 100 handwritten) in mid-2001. The errors detected are summarised in the Box. The same medical staff were responsible for both types of prescriptions. Significantly more errors in prescribing were noted for the computer-generated prescriptions than for the handwritten scripts (P < 0.001). The proportion of errors with potential for harm was similar in both groups. Three specific types of error occurred more frequently with electronic prescribing. We can speculate that dosing errors occurred when previous discharges were copied and the previous dose was continued, duration errors occurred as a result of a computer default to 10 days’ therapy, and the continuation of drugs not required for discharge resulted from copying previous medication records and not reviewing the current drugs prescribed. This uncontrolled observational audit demonstrated that electronic prescribing without decision support in busy medical wards can significantly increase the risk of patient harm when compared with the handwritten system. The discharge prescription component of this system was withdrawn on the basis of this audit, and the paper-based system reinstituted until a safer alternative becomes available. 1: Comparison of error rates with electronic and handwritten discharge prescribing systems Examples of prescribing errors Computer Handwritten Number of prescriptions 100 100 Number of drugs 700 605 Omissions Warfarin and irbesartan omitted 12 16 Duplications Spironolactone and atorvastatin duplicated 2 0 Dosing errors Prednisolone 50 mg in the morning for 10 days ordered: should have been reducing by 10 mg every second day 25 5 Drug errors Diltiazem oral 60 mg three times a day ordered: should have been diltiazem slow release 180 mg in the morning 4 4 Drug name unclear Fluticasone inhaler: no strength 6 0 Duration error Antibiotics intended for 3 or 5 days: ordered for 10 days (default quantity) 13 1 Drug not required on discharge Frusemide 80 mg twice daily was continued: the drug had been stopped during admission 15 4 Route error Glyceryl trinitrate 5 mg oral ordered: patch was the intended form of drug 3 0 Frequency error Carvedilol ordered for mornings: had been twice daily in hospital 1 0 Total number of errors 81 30 Error rate per item 11.6% 5.0%

Ian D Coombes · Danielle A Stowasser · Charles A Mitchell · Paul Varghese

Jane Turner,* Brian McAvoy,† Karen Luxford,‡ Jane Fletcher§ * Senior Lecturer, Department of Psychiatry, University of Queensland, Herston, QLD; † Deputy Director, § Senior Project Officer, National Cancer Control Initiative, Carlton, VIC; ‡ Program Director, National Breast Cancer Centre, Camperdown, NSW. jane.turnerATuq.edu.au To the Editor: The Supplement on palliative care (15 Sep 2003) provided a welcome overview of this critical area of clinical practice. 1 Many of the articles emphasised the generalist nature of palliative care and the importance of multidisciplinary care and teamwork. Recently published guidelines2 now provide evidence-based information on psychosocial aspects of care for health professionals working in the field, as well as surgeons, radiation oncologists, medical oncologists, general practitioners, nurses, social workers, psychologists, psychiatrists, physiotherapists and occupational therapists. These are the world’s first comprehensive, evidence-based guidelines on the social, psychological and economic impacts of cancer and how these can be better prevented, managed and treated by health professionals. They cover the whole spectrum of cancer care, from diagnosis through to treatment and palliation. The guidelines are based on comprehensive and systematic reviews of the international research literature and an extensive consultative process to ensure their clinical relevance. Developed by the National Breast Cancer Centre and the National Cancer Control Initiative (NCCI) and funded by the Federal Government, the guidelines were approved by the National Health and Medical Research Council (NHMRC) in April 2003. The guidelines cover the most commonly occurring cancers: colorectal, breast, gynaecological, head-and-neck, lung, pancreatic, prostate and urogenital cancers, and melanoma and non-Hodgkin’s lymphoma. Recommendations for clinical practice are rated according to NHMRC levels of evidence.3 Four main areas are addressed by the guidelines: understanding the challenges of cancer and how people react; provision of care by the treatment team to all patients with cancer; referral for specialised care; issues requiring special consideration — culture, age, geography and sexual orientation. The guidelines were developed to assist health professionals in supporting adult cancer patients. This includes providing information and choice to patients, helping them deal with procedures and treatments, providing emotional and social support, ensuring continuity of care, and dealing with specific concerns that may arise, including anxiety and depression. The guidelines can be accessed at the NCCI’s website (www.ncci.org.au), or hard copies can be obtained from the National Breast Cancer Centre.

Jane Turner · Brian McAvoy · Karen Luxford · Jane Fletcher

David J Blacker Neurologist and Stroke Physician, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009. davidblackermdAThotmail.com To the Editor: I respect the opinion of Hoffman1 and others who have recently expressed concerns about the use of tissue plasminogen activator (tPA) in patients with ischaemic stroke. However, it is critical that these views do not dampen the enthusiasm for better stroke treatments. The Therapeutic Goods Administration recently approved tPA for ischaemic stroke patients with symptoms of less than 3 hours’ duration. This approval has catalysed collaboration between stroke units around Australia and may provide benefits to patients who do not receive tPA, by improving clinical pathways, as well as a more coordinated approach to treatment. Internationally acclaimed Australian stroke experts have already rebutted the arguments of opponents of the National Institute of Neurological Disorders and Stroke (NINDS) trial, 2,3 and an independent reanalysis of the NINDS data showed tPA to be more effective than originally reported.4 It is time to stop bickering about the NINDS trial5 and move forward, by focusing on a collaborative effort between emergency departments and stroke teams. In the near future, there will surely be better data on new-generation thrombolytics and other agents; all will operate on similar “time is brain” protocols, as did the NINDS trial. Obviously, more data would be useful, but when clinicians are faced with patients with acute stroke today they must give the patients and their families the facts about tPA, regardless of their personal opinion. These are best expressed in terms of the absolute risk reduction for disability seen in the NINDs trial. It is interesting to note the widespread discomfort with the 6.4% risk of intracerebral haemorrhage (half of which were fatal) in this trial of a “medical” therapy. Surgeons quote similar morbidity and mortality risks every day to patients undergoing procedures such as coronary artery bypass grafting. Additionally, many surgical procedures became established on much less solid evidence than the NINDs trial, and yet there is no outcry. For example, many thousands of carotid endarterectomies were performed before the publication of controlled-trial data. In properly selected patients in expert hands, we now have a treatment that works. Its risks should not be underestimated, but should also be placed into context when compared with other powerful therapies for serious illnesses. Patients presenting with acute ischaemic stroke in Australia today have the chance to benefit from tPA, but future patients will benefit even more, partly because of the process that is being undertaken to institute pathways for using this drug.

David J Blacker

Jerome R Hoffman Professor of Medicine and Emergency Medicine, UCLA School of Medicine, Los Angeles, California, USA. jrhATucla.edu In reply: I agree with Blacker that enthusiasm generated by thrombolytic therapy could lead to benefit for stroke patients, independent of whether the therapy is actually useful, or even whether they receive it. However, I believe there are better ways to encourage rational stroke care. I also acknowledge that some experts believe thrombolysis is proven to be beneficial if used in accordance with NINDS (National Institute of Neurological Disorders and Stroke) guidelines. Others believe the question is not yet settled and are concerned that widespread adoption of the guidelines will lead to more harm than good. It is one thing to enthuse about possible benefits of a treatment, particularly for a devastating disease for which we have traditionally had little to offer. It is entirely different to embrace this therapy, even though it may be harmful overall, simply out of this frustration. I disagree with Blacker that the best way to inform patients about thrombolysis is “in terms of the absolute risk reduction for disability seen in the NINDS trial”. Regardless of concerns about the trial itself, it is always foolhardy to accept data from one small study as “the truth”. Many other trials have found far worse results — it would be equally inappropriate to base all estimates on their worst outcomes. Finally, there is strong evidence that, even if NINDS-like “success” could be achieved under optimal circumstances, routine use in the community might well lead to overall harm. I am also cautious about Blacker’s comparison of thrombolysis and some surgical procedures in terms of adverse effect rates. No single adverse effect rate is or is not acceptable for all interventions — a 90% rate of intracerebral haemorrhage could be acceptable in a disease with 100% mortality, while a 2% rate would be completely unacceptable in a disease with no long-term morbidity. Furthermore, the adoption of many surgical interventions in the absence of persuasive evidence does not justify repeating this mistake. Of course we must routinely make decisions without definitive evidence, based on our best estimates of benefits and harms. We should never take such decisions lightly, and should in general embrace the precautionary principle, which tells us not to adopt new therapies without reasonable evidence of their safety (especially when any benefit is likely to be extremely small). Although some advocates support thrombolysis based on current knowledge, my reading of available evidence is far less sanguine. That is why I continue to argue that this treatment should not be introduced into routine practice until far better evidence of its benefit outweighing its harm becomes available. Given the possibility that this treatment will harm stroke patients overall, and the likelihood that any potential benefit is very limited for the stroke population as a whole, I ask once again, why is so much being made of so little?

Jerome R Hoffman

Matthew T Naughton,* Darren R Mansfield,* David M Kaye,† Peter Bergin,† Meroula Richardson† * Respiratory Physician, † Cardiologist, Alfred Hospital, PO Box 315, Prahran, VIC 3181. m.naughtonATalfred.org.au To the Editor: We were surprised that Campbell’s recent article on heart failure1 made no mention of sleep apnoea. This is despite the fact that about 50% of heart failure patients have sleep apnoea (either central or obstructive) and that quite a large body of literature now supports a causative relationship between obstructive sleep apnoea and congestive heart failure, supported by recent authoritative reviews. 2-4 Canine studies have shown that, in the absence of any other variable, obstructive sleep apnoea results in left ventricular systolic and diastolic dysfunction. Importantly, the impact of continuous positive airway pressure (CPAP) in acute cardiogenic pulmonary oedema and subacute pulmonary oedema (central sleep apnoea) and heart failure in the setting of obstructive sleep apnoea are not mentioned. Identification and treatment of sleep apnoea in people with heart failure is supported by a trial we have recently conducted in which significant improvements in quality of life and objective markers of cardiac function were seen in patients treated with nasal CPAP.5

Matthew T Naughton · Darren R Mansfield · David M Kaye · Peter Bergin · Meroula Richardson

Duncan J Campbell Senior Research Fellow, St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, VIC 3065. J. CampbellATmedicine.unimelb.edu.au In reply: I am grateful to Naughton and colleagues for their contribution to the debate about how we might prevent the epidemic of heart failure. I agree that both obstructive and central sleep apnoea are frequently associated with heart failure and that treatment of sleep apnoea can improve cardiac function. However, as indicated by its title, my article focused on how we might prevent heart failure. Central sleep apnoea in heart failure is usually the consequence of the heart failure.1 Heart failure may contribute to obstructive sleep apnoea as well,2 and obstructive sleep apnoea may, in turn, be an important contributor to heart failure pathogenesis. Epidemiological evidence links obesity with hypertension and obstructive sleep apnoea.3 Significant sleep apnoea is present in about 40% of obese people, and about 70% of people with obstructive sleep apnoea are obese.3 Obesity and obstructive sleep apnoea may each contribute to one another, and both may contribute to hypertension. The need to prevent obstructive sleep apnoea is an argument for more effective prevention of obesity. In addition to reducing its metabolic consequences, preventing obesity is likely to reduce the incidence of hypertension and obstructive sleep apnoea, and to thereby decrease the incidence of heart failure. For people with obstructive sleep apnoea not caused by obesity, alternative strategies will be required to prevent and treat the sleep apnoea and thus prevent its consequences.

Duncan J Campbell