Pharmacology

To the Editor: Pseudoephedrine is no longer a banned substance in sport.1 It was originally banned to protect athletes from overuse and its dangers. Has it become harmless or are athletes more intelligent? This highlights much of the confusion in drug testing. Athletes with diabetes are permitted to use insulin for therapy, but those with hypertension are not allowed to take β-blockers. Both drugs are popularly believed in athletic circles to improve performance. What is to stop an athlete with diabetes from taking extra insulin for performance enhancement? Why do we discriminate against those with hypertension? There is a ban on oxygen-transport drugs and on physical environment enhancers such as hypobaric chambers. Both are alleged to produce the same result, but only use of the drug can be tested. The penalty for the drug user is disqualification, but for the hypobaric enthusiast a rousing cheer for a drug-free effort. The crime is the same, so why vary the penalty? There is never likely to be a level playing field under the present system, in which one reads of positive test results being swept under the table. How will drug testing eliminate the genetic inequalities between athletes? How will testing improve the availability of top-level coaches and training facilities to all? How can it eliminate the inequality in financial incentives, allowing some athletes to train for 6 hours daily while others have to work to enable them to train for even 2 hours daily? We have swimming costumes that decrease drag in the water,1 resulting in faster times. These are not universally available, giving their owners an advantage. A level playing field will never exist in our present system. It is incongruous that in all this mess, only drugs are available to all. The current frenzy to test blood has ethical problems which have not been addressed.2 What is to happen to an athlete who develops an infection from a dirty needle? Who is responsible for the tester who has a needlestick injury from an HIV-positive athlete? It is worth remembering that this diagnosis will only be made 3 months after the Games, when everyone has dispersed. The whole area needs to be reviewed by an outside body with no vested interest in the outcome.

Anthony P Millar

For most warfarin indications, the target maintenance international normalised ratio (INR) is 2–3. Risk factors for bleeding complications with warfarin use include age, history of past bleeding and specific comorbid conditions. To reverse the effects of warfarin, vitamin K1 can be given. Immediate reversal is achieved with a prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP). Vitamin K1 is essential for sustaining the reversal achieved by PCC and FFP. When oral vitamin K1 is used for warfarin reversal, the injectable formulation of vitamin K1 is preferable to tablets because of its flexible dosing; this formulation can be given orally or injected. To temporarily reverse the effect of warfarin when there is a need to continue warfarin therapy, vitamin K1 should be given in a dose that will quickly lower the INR to a safe, but not subtherapeutic, range and will not cause resistance once warfarin is reinstated. Prothrombinex-HT is the only PCC approved in Australia and New Zealand for warfarin reversal. It contains factors II, IX and X, and low levels of factor VII. FFP should be added to Prothrombinex-HT as a source of factor VII when used for warfarin reversal. Simple dental or dermatological procedures may not require interruption to warfarin therapy. If necessary, warfarin therapy can be withheld 5 days before elective surgery, when the INR usually falls to below 1.5 and surgery can be conducted safely. Bridging anticoagulation therapy for patients at high risk for thromboembolism should be undertaken in consultation with the relevant experts.

Ross I Baker PhD, FRACP · Paul B Coughlin PhD, FRACP, FRCPA · Hatem H Salem MD, FRACP, FRCPA · Alex S Gallus FRACP, FRCPA, FRCP · Paul L Harper MD, FRACP, FRCPA · Erica M Wood FRACP, FRCPA

During a diverse career as pharmacist, research synthetic chemist, pharmacologist and medical practitioner, George Eckert was always a charismatic teacher across this diverse knowledge base. He strongly influenced generations of students, doctors, dentists, and pharmacists through coaching, tutoring, mentoring, lecturing and published research. George was born in Sydney on 24 October 1931. He was educated at Sydney Boys’ High School, and studied pharmacy at the University of Sydney, graduating in 1951. After spectacular success as a pharmacy academic at the University of Sydney and private tutor to over 1000 students from 1953 to 1965, George changed direction and studied medicine, graduating with honours in 1968. He trained in the Department of Clinical Pharmacology at St Vincent’s Hospital, then, from 1974 to 1980, directed the first NSW Health Commission-funded Clinical Pharmacology unit at Sydney Hospital. In 1984, he transferred to St George Hospital, Kogarah, where he stayed until his retirement in 1992. During this time, he was responsible for changing methods of prescribing and managing drugs in hospitals and for instituting quality-assurance and risk-management procedures that are now benchmark best-quality practice worldwide in all areas of medical practice and healthcare delivery. He influenced the flow of information about drugs, believing that those who prescribed, administered and dispensed them, and the people who received them, were all entitled to more information about their use and effects than they were getting. He engaged in what he called “counter-detailing”: giving practitioners a view of drugs independent of that supplied by pharmaceutical companies, and often at odds with it. He was fearless and selfless in the public interest, passing up lucrative offers from pharmaceutical companies that were widely available to clinical pharmacologists and other medical specialists in that period. George had the many gifts and true modesty of a polymath. He had a creative intellect, bringing together his diverse education and life-long learning. The examiners for his Doctor of Medicine thesis wrote: “This thesis is to be highly commended, as it is so novel. It is so far ahead of the prevailing orthodoxy conceptually that it is not likely to be widely understood or appreciated until there is a broadening of pharmaceutical and pharmacological training.” He had an encyclopaedic knowledge of history (ancient and modern), music, opera, film, chess and cricket, and shared these interests with friends of all ages. George’s greatest gift was his capacity for friendship with a wide range of people in his diverse life roles. He saw the world as one moulded by human strengths and weaknesses, and shared his insights with kindness, compassion and humour. Towards the end of his life, suffering from prostate cancer, he faced his illness with stoicism, dignity and courage, and died at home among family and friends on 17 May 2004. Allan J McLean, Lisa L Demos, Constantine G Berbatis

Allan J McLean · Lisa L Demos · Constantine G Berbatis

There is yet no convincing evidence that testosterone therapy is safe or effective in counteracting any effects of ageing One of the most challenging and time-consuming aspects of medical practice is discussing with patients what they have gleaned from the Internet or popular lay publications. One topic of such discussion is the use of testosterone in male ageing, with public interest fuelled by persuasive publications like Maximising manhood,1 The testosterone revolution2 and Male menopause.3 Much of the information gained from these books may seem to be very convincing, but is, at best, “ahead of the evidence”. It is often difficult for doctors not to appear old-fashioned, ignorant or downright contrary when showing scepticism or advising caution in the face of such conviction. . . . beware when entrepreneurial business ventures overtake evidence-based medicine. In this issue of the Journal, Handelsman (page 419) has documented temporal and regional trends in testosterone prescribing in Australia.4 He has shown increases in prescribing corresponding to popular promotion of androgen therapy in ageing. This rise has been particularly marked in Western Australia, coincident with the opening in that state of entrepreneurial clinics aimed at the ageing-male market. There is no doubt that testosterone therapy benefits patients with documented hypogonadism associated with conditions such as Klinefelter’s syndrome and hypopituitarism. Current prescribing guidelines allow for this, regardless of age. However, for the use of testosterone in men of middle age and older with borderline low serum levels of testosterone, the evidence for both efficacy and safety is yet to be established. The original description of the efficacy of testosterone therapy for the vicissitudes of age has been shown to be no more than a powerful placebo effect.5 Nevertheless, it would seem that those who espouse testosterone therapy in this setting have identified an expanding market. The Australian population is ageing: 28% of men are over the age of 50 and 12% over the age of 65 years. It is projected that by 2021, 4.0 million Australians will be over the age of 65, an increase of 1.7 million from today’s estimate.6 Together with a documented fall in testosterone level with age, where it is estimated that 20% of men over the age of 60 will have a testosterone level below the reference range, this predicts a large population of men as potential customers for androgen therapy.7,8 Although most studies have shown a gradual decline in testosterone level with age, the clinical consequences of this are not known. Conditions such as muscular frailty, loss of bone mass, cognitive decline and erectile dysfunction are also age related, but whether testosterone deficiency has a causal role is not clear. More importantly, it has not yet been established that testosterone therapy has any role in correcting these conditions. It has been a widely held belief that androgen deficiency is a common and correctable cause of erectile dysfunction. However, in a cohort of 1455 men presenting with erectile dysfunction, we found that testosterone deficiency constituted a correctable cause in only 3%.9 All of those who responded to testosterone therapy for erectile dysfunction had a testosterone level < 7 nmol/L, well below the reference range of 11–37 nmol/L. The use of testosterone therapy in patients with normal or slightly depressed androgen levels seems to be of little benefit.10 A similar finding has been documented in the response of bone density to testosterone therapy. The largest and longest-term study in this setting examined testosterone treatment in 108 men aged over 65 years with a baseline testosterone level more than 1 standard deviation below the young adult mean (ie, < 16.5 nmol/L).11 Lumbar spine bone density rose significantly only in those with a baseline testosterone level below the reference range (ie, below 10 nmol/L). Another, smaller study has shown a significant increase in lumbar spine density with androgen therapy in men with a baseline testosterone level < 12.1 nmol/L.12 Muscle mass and strength decrease with age, and it is tempting to link this with the decline of testosterone. In hypogonadal men, testosterone therapy improves muscle strength. In men aged over 65 years, testosterone treatment leads to a fall in fat mass and a rise in lean body mass, together with a perception of increased strength. However, although a perception of improved muscle function was reported, no objective change in measured physical function, such as walking or stair climbing, knee flexion or in muscle strength as measured by dynamometer, was demonstrated.13,14 The safety of sex hormone therapy in menopausal women, used widely for the last 60 years, has recently been scrutinised and reassessed.15 Knowledge about the safety of sex hormone replacement in men is, by contrast, in its infancy. No studies have been conducted for long enough to identify the long term risks of androgen therapy in ageing. Because of lack of statistical power in studies, it is not known whether testosterone use will increase the incidence of androgen-dependent disease such as prostate cancer, although a sustained rise in prostate-specific antigen level has been observed.13 Two other side-effects of testosterone treatment have been identified in short term studies, namely an increase in obstructive sleep apnoea and increased haematocrit and polycythaemia, both of which may have implications for cardiovascular risk.13,16 Handelsman has documented the effect on testosterone prescribing of entrepreneurial clinics aimed at the ageing-male market.4 Daily, we see advertisements for similar commercial enterprises which deal in unregistered and/or unproven prescribing, including DHEA (dehydroepiandrosterone) or testosterone to men and women, progesterone cream, and lozenges of variable mixes of oestrogens, progestins and androgens. We should beware when entrepreneurial business ventures overtake evidence-based medicine. What is needed now regarding testosterone therapy in ageing are large, long-term, prospective, randomised, placebo-controlled studies to establish if there is, indeed, benefit for specific symptoms and to identify potential risks.17

Bronwyn GA Stuckey BA, FRACP

Objectives: To analyse temporal trends and geographical variations in testosterone prescribing in Australia.Design and setting: An analysis of testosterone prescribing over the past 11 years according to products and region, determined by Pharmaceutical Benefits Scheme (PBS) expenditure in Australian states and territories.Main outcome measure: Patterns of monthly PBS expenditure on injectable, oral and implantable testosterone products from 1 January 1991 to 30 December 2001, classified by state or territory.Results: There were two periods (1993–1994 and 1998–1999) of striking upsurge followed by declines in national total prescribing of testosterone. These changes were more prominent for oral than injectable testosterone products, and patterns were similar in all regions, apart from a disproportionately higher peak in Western Australia in 1998. On a per-capita basis, Western Australia showed a dramatic increase in prescribing of oral and implantable, but not injectable, testosterone coinciding with the opening of a franchised men’s sexual health clinic in Perth.Conclusion: The two striking upsurges in testosterone prescribing despite no convincing new evidence to justify them appear to reflect promotional activity to prescribe testosterone for older men, rather than overcoming the underdiagnosis of androgen deficiency related to pituitary or testicular disease in younger men. The curtailments after the introduced restrictions to PBS prescribing for older men without overt androgen deficiency were partial and temporary, suggesting that such regulatory barriers are only partly successful in counteracting the commercial and populist pressure driving excessive testosterone prescribing. Professional and community education is needed for appropriate diagnosis of genuine androgen deficiency in younger men, while discouraging unproven testosterone treatment for ageing men.

David J Handelsman FRACP, PhD

Melagatran is a synthetic, small-peptide direct thrombin inhibitor with anticoagulant activity. Ximelagatran, an oral prodrug, undergoes rapid enzymatic conversion to melagatran. Melagatran has rapid onset of action, fixed twice-daily dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring drug levels or dose adjustment. There is no specific antidote, but the drug has a short plasma elimination half-life (about 4 hours). In clinical studies, melagatran/ximelagatran is not inferior to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, to heparin–warfarin for acute treatment and extended secondary prevention of deep vein thrombosis, and superior to warfarin for prevention of venous thromboembolism after major orthopaedic surgery. Major bleeding with melagatran/ximelagatran occurred at rates similar to those in patients treated with warfarin. 6%–12% of patients taking ximelagatran develop asymptomatic elevated liver enzyme levels (predominantly alanine aminotransferase) after 1–6 months of therapy; this usually resolves with cessation of therapy. Less than 1% of patients develop abnormal liver function while taking ximelagatran; this rarely persists or develops into clinical illness.

Timothy A Brighton FRACP, FRCPA, MD

Christine Y Lu,* Kenneth M Williams,† Lyn March,‡ James V Bertouch,§ Richard O Day¶ * PhD Candidate, † Deputy Director, ¶ Director, Therapeutics Centre, St Vincent’s Hospital, University of New South Wales, Victoria St, Darlinghurst, Sydney, NSW 2010. ‡ Rheumatologist, Royal North Shore Hospital, The University of Sydney, St Leonards, NSW. § Head, Department of Rheumatology, Prince of Wales Hospital, Randwick, NSW. christine.luATstudent.unsw.edu.au To the Editor: The tumour necrosis factor (TNFα) inhibitors etanercept, infliximab and adalimumab are new treatments for rheumatoid arthritis (RA) subsidised by the Pharmaceutical Benefits Scheme (PBS) under strict criteria. These are based on data supplied by the sponsors and protracted discussions between the stakeholders: the Pharmaceutical Benefits Advisory Committee (PBAC), the sponsors, rheumatologists and consumer representatives.1 One eligibility criterion is that adult patients must be or have been rheumatoid-factor positive. This requirement raises particular concerns. Rheumatoid factor is not exclusively associated with RA. It is found in a number of other autoimmune and infectious diseases, and has been detected in healthy people. Rheumatoid factor is a serological criterion in the American College of Rheumatology classification for RA. However, its presence is not definitive for a clinical diagnosis of RA, with rheumatoid factor being absent in about 30% of patients with RA. Studies suggest that patients who test positive for rheumatoid factor at baseline are more susceptible to relatively severe expression of RA, with development of erosions and functional disability.2 As the PBS already limits access to TNFα inhibitors to patients with severe active RA, the predictive value of rheumatoid factor for severity is redundant. We systematically reviewed 23 clinical trials of TNFα inhibitors available in the public domain (references available on request). The review showed that only the Early Rheumatoid Arthritis trial restricted recruitment to patients who tested positive for rheumatoid factor.3 The aim of this study was to examine the effect of etanercept on the rate of development of erosions in patients with early RA, not whether rheumatoid-factor status affected response. We conclude that the evidence for an association between rheumatoid-factor status and response to TNFα inhibitors in patients with severe RA is inadequate to justify rheumatoid-factor status as a criterion for PBS subsidisation. Similarly, no evidence for an association between rheumatoid factor and response to disease-modifying anti-rheumatic drugs has been reported.4 Nevertheless, potential predictors of response to TNFα inhibitors and such drugs are emerging (eg, polymorphisms of HLA-DRB1, TNFα, and interleukin-10).5 Further analysis of the unpublished individual patient data held by the sponsors is needed to shed light on this question. Clinical studies specifically designed to evaluate the influence of rheumatoid-factor status on response would be helpful. The PBAC may have been provided with these data, but patients and clinicians operating in the public domain have not. This gives rise to an ethical dilemma whereby prescribers cannot provide a plausible explanation for why rheumatoid-factor status is an access criterion. For example, if rheumatoid-factor-positive status was selected to exclude patients with rheumatoid-factor-negative psoriatic arthritis, then the rationale would not appear to be ethically sound. Greater transparency with respect to the rationale and the evidence for the criteria selected for targeting subsidised access to important high-cost pharmaceuticals will enhance confidence in the PBS process.

Christine Y Lu · Kenneth M Williams · Lyn March · James V Bertouch · Richard O Day

Lloyd N Sansom Chair, Australian Pharmaceutical Benefits Advisory Committee, School of Pharmacy, University of South Australia, Adelaide, SA 5000. Lloyd. SansomATunisa.edu.au Comment: I am grateful for the opportunity to put the perspective of the Pharmaceutical Benefits Advisory Committee (PBAC) on this important issue for patients and prescribers using TNFα inhibitors for rheumatoid arthritis. I can confirm that the PBAC based its recommendation to exclude patients who test rheumatoid-factor negative on a meta-analysis of the data presented to it in the sponsor’s reports of two published randomised trials.1,2 The sponsor of etanercept requested a restriction that limited use to patients with rheumatoid-factor-positive status — a proposition that was queried by the PBAC in its evaluation. The sponsor indicated in its response that rheumatoid-factor status was a treatment-effect modifier. As anticipated by Lu and colleagues, the reason for the recommendation was neither to confirm the diagnosis of rheumatoid arthritis nor an attempt to identify patients with more severe disease. The main reason is that there was some statistical support for the contention that, in patients with rheumatoid arthritis, being rheumatoid-factor positive is associated with a better response to treatment with these drugs. Unfortunately, my request to the sponsor to be able to release in this letter the information on which the decision was based was refused. The statistical analysis relied on by the PBAC was based on individual patient data, stratifying trial participants into two groups (rheumatoid-factor positive and rheumatoid-factor negative), and then formally applying a test for interaction against the reported treatment effect compared with placebo. Although a post-hoc analysis, this approach has the advantage of relying on the entire trial dataset rather than increasing the likelihood of detecting spurious differences by conducting a series of post-hoc sub-group analyses. It also differs from the systematic review reported by Lu and colleagues, which sought to examine the question based on the reported eligibility criteria of the trials, and therefore could only be conducted at the level of the overall trial, not the level of the individual patient in the trials. The interpretation of the data available to the PBAC at the time was supported by rheumatologists advising the PBAC about actual restrictions for the subsidy of these expensive agents. It is perhaps noteworthy that many decisions that guide treatment are made purely on the basis of biological plausibility. On this occasion, there was some statistical support, albeit from a post-hoc analysis, to support any biological arguments. There is inevitably an element of judgement about these decisions, as is clear in the letter from Lu et al, who describe “accumulating evidence” in relation to whether gene polymorphisms “may be predictive of clinical responsiveness”. The current situation, as exemplified in this letter, in which the PBAC is unable to give detailed reasons for its decisions, clearly demonstrates the urgent and critical need for greater transparency of the PBAC processes, and underscores the fundamental right of Australian consumers and prescribers to information relevant to decisions about the subsidy of medicines in this country. The PBAC is willing to examine any new evidence relating to the influence of rheumatoid-factor status on health outcomes and the cost-effectiveness of these agents. If there is additional evidence supporting a review of the current listing, the PBAC would encourage the sponsors of these drugs to prepare appropriate submissions to enable us to evaluate these data. As Chair of the PBAC, I intend to continue to work towards the goal of greater transparency, whereby the outcome of any such new evaluation, and its basis, could be made available to Australian consumers and prescribers.

Lloyd N Sansom

Peter J Gilbar,* Christine V Carrington† *† Co-Chair, Committee of Specialty Practice in Oncology, The Society of Hospital Pharmacists of Australia, Suite 3, 27-33 Raglan Street, South Melbourne, VIC 3205. peter_gilbarAThealth.qld.gov.au To the Editor: The national media recently highlighted the tragic consequences of the inadvertent spinal administration of the antineoplastic drug vincristine. The 7.30 Report (ABC Television) detailed the case of a young man erroneously administered vincristine intrathecally instead of, as intended, intravenously, resulting in progressive neurotoxicity, paralysis and death.1 Since the first report in 1968 of unintentional intrathecal administration of vincristine,2 many, invariably fatal, cases have been described. These have involved a combination of human and system errors affecting the medical, nursing and pharmacy professions. On behalf of the Society of Hospital Pharmacists of Australia, we recommend the following strategies to reduce the opportunity for error: Only specifically trained and designated oncology staff should prepare, dispense and administer cytotoxic medication. Intrathecal chemotherapy should only be administered during normal working hours, and in an area where no other cytotoxic drugs are given or stored. Medical staff must use a formal checking procedure, involving an oncology-trained nurse, to ensure the right drug is given at the right dose, by the right route, to the right patient. Intrathecal drugs must be packaged separately and clearly labelled both on the syringe and outer container “For intrathecal use”. Specifically designated containers should be used for transportation of intrathecal drugs from the pharmacy and for storage on the ward. Intrathecal doses should be delivered separately and preferably administered after drugs to be given by other routes have been supplied to the ward and administered. Vincristine should be prepared in a small-volume intravenous bag rather than a syringe.3 For adults, prepare vincristine in an intravenous bag in 50 mL of sodium chloride 0.9% and administer it as a short intravenous bolus over 5–10 minutes. Smaller volumes and a slower administration rate are suggested for children. While this method has been criticised as potentially increasing the risk of extravasation injury, this has not been reported as a problem. Vincristine should be clearly labelled both on the intravenous bag and outer container “For intravenous use only — fatal if given by other routes”. Negative labels, such as “Not for intrathecal use”, must never be used. Many hospitals currently use syringes for vincristine and increase the diluent volume in the syringe as a deterrent to intrathecal administration; however, fatalities have occurred after the administration of vincristine supplied in 10 mL4 and 20 mL5 syringes. The safest method of eliminating the potential for spinal instillation of vincristine remains the abolition of the syringe as a means of administration.

Peter J Gilbar · Christine V Carrington

Leonie Segal,* Richard H Osborne,† Susan E Day‡ * Deputy Director, ‡ Research Fellow, Health Economics Unit, Monash University, PO Box 477, West Heidelberg, Melbourne, VIC 3081. † Senior Lecturer, Centre for Rheumatic Diseases, University of Melbourne, Melbourne, VIC. Leonie. SegalATbuseco.monash.edu.au In reply: The “transfer to utility” TTU technique was devised to compare disparate interventions, using published clinical trial literature, where utility data are not reported. While collection of utility data in clinical trials would be preferable, until this occurs routinely a means to translate reported quality-of-life scores into utility scores is highly useful. Other groups are also grappling with this.1 In developing the TTU weights, various sophisticated statistical techniques were explored. However, added complexity did not improve the estimates. Contrary to the suggestion by Viney and colleagues, the TTU estimates are highly plausible and were vetted by our reference panel of clinical experts. Taking the example Viney and colleagues cite, a 0.304 increase in utility score for hip replacement indicates a patient would, on average, be willing to forgo 30.4% of remaining life-years to obtain the benefits of surgery — not 40% as incorrectly stated by Viney et al. This is consistent with the large increase in well-being observed following hip replacement (in the seminal trial, SF-36 mean scores increased from 26.9 to 66.6 for physical function, 14.6 to 58.7 for role physical, and 32.9 to 72.8 for bodily pain). Whether the TTU introduces bias (a characteristic of other summative approaches to estimating health, such as the popular DALYs) is a matter for future research. Undoubtedly, all population-wide approaches suppress specific information, but the purpose of the priority-setting model supported by the TTU is not to provide information on individuals, but to compare management options to give clinicians and policymakers another way of understanding the comparative performance of disparate interventions.

Leonie Segal · Richard H Osborne · Susan E Day

Chris G Fenn Medical Consultant, Pfizer Australia Pty Ltd, 38–42 Wharf Road, West Ryde, NSW 2114. chris.fennATpfizer.com To the Editor: At Pfizer, we are very concerned about major conclusions drawn with regard to cost-effectiveness of COX-2- specific inhibitors (CSI) in the article by Segal and colleagues;1 these conclusions are based on an entirely inadequate and inappropriate database. The CSI cost-effectiveness analysis is based on two publications described by Segal et al as “seminal”,2,3 and on a British Medical Journal editorial described as “a report by the US FDA [United States Food and Drug Administration]”.4 The first of the two “seminal” publications was a pivotal study for registration purposes;2 the second was neither pivotal nor “seminal”.3 The purported “report by the FDA” presents the authors’ opinion of a single study5 which does not reflect the overall body of gastrointestinal (GI) safety data for either CSI or non-steroidal anti-inflammatory drugs. The issues with this study and the inaccuracies in the editorial have been reported.6 Segal et al1 have apparently ignored at least 20 other publications (references available on request) comparing the safety and efficacy of celecoxib with NSAIDs; we would consider these relevant to any valid analysis of cost-effectiveness. There are probably a similar number of relevant publications for the second CSI, rofecoxib, which should also be considered if an analysis of the CSI class is to be rigorous. The body of evidence (previously summarised7) shows that CSIs are associated with a 50% or lower incidence of serious GI complications than non-specific NSAIDs, which results in lower mortality. Any cost-effectiveness analysis that ignores this GI safety advantage of CSIs over NSAIDs is incomplete. Therefore, the conclusions by Segal et al that “Non-specific NSAIDs and COX-2 NSAIDs were found to perform similarly in terms of outcomes and side effects . . .” and “ . . . In most scenarios, COX-2 NSAIDs are dominated by non-specific NSAIDs”1 are not true reflections of either the trial data nor real-world clinical practice, and may mislead the medical community as to the relative safety of these agents. It is important to note that the full body of celecoxib data has been submitted by Pfizer as a cost-effectiveness analysis to the Pharmaceutical Benefits Advisory Committee (PBAC). Contrary to the conclusions of Segal et al, in every scenario in the PBAC submission celecoxib was more cost-effective than non-specific NSAIDs. Celecoxib is currently listed on the Pharmaceutical Benefits Scheme and this indicates that it was considered cost-effective. An abstract has been published regarding the cost-effectiveness of celecoxib in the Australian setting.8 We consider that every statement made in the article by Segal et al with regard to the cost-effectiveness of COX-2-specific inhibitors1 is inaccurate and misleading, as it is not based on the available evidence. We request a retraction statement from the authors.

Chris G Fenn

Leonie Segal,* Richard H Osborne,† Susan E Day‡ * Deputy Director, ‡ Research Fellow, Health Economics Unit, Monash University, PO Box 477, West Heidelberg, Melbourne, VIC 3081. † Senior Lecturer, Centre for Rheumatic Diseases, University of Melbourne, Melbourne, VIC. Leonie. SegalATbuseco.monash.edu.au In reply: Our economic analysis of COX-2-specific inhibitors (CSIs) was part of a research program on priority setting. The application to osteoarthritis (OA) involved cost–utility analyses of 19 interventions (written up in a 195-page research report1), and was subject to peer review by an advisory panel including senior clinicians. The research drew on over 200 references, 23 on CSI, but a limit of 50 references for articles in the Medical Journal of Australia meant that full referencing was not possible. Evidence of efficacy in OA and adverse events (gastrointestinal and cardiac) are incorporated in our QALY estimates, the latter based primarily on the seminal CLASS trial (Celecoxib Long-term Arthritis Safety Study), and the United States Federal Drug Administration (FDA) analysis2-4 of this trial (summarised previously5). The FDA report concludes that for the primary endpoint specified in the study protocol — clinically significant upper gastrointestinal event (CSUGIE) — for the entire study period there was no significant difference in adverse events between the celecoxib arm and the combined diclofenac/ibuprofen arms (P = 0.45).2 Using the broader definition — combined CSUGIE and gastroduodenal ulcer (CSUGIE/GUD) — a significant difference is reported between combined non-specific non-steroidal anti-inflammatory drugs (NSAIDs) and celecoxib (P = 0.040), but not with diclofenac (P = 0.295).2 The FDA concluded that “celecoxib was not able to demonstrate it was statistically superior to diclofenac in terms of the clinically important UGI [upper gastrointestinal] endpoints and conditions defined in this study. The same is not true when comparisons are made to ibuprofen.”2 The dominance of non-specific NSAIDs reflects celecoxib priced at $32.13/month (for 200 mg/day) and diclofenac at $13.42/month (for 75 mg/day)6 and evidence of equivalence in management of OA and GI side effect profile. We agree this does not support a conclusion about class dominance. All NSAIDs and all CSIs are not the same. Celecoxib is listed on the Pharmaceutical Benefits Schedule, but, as submissions by companies to the Pharmaceutical Benefits Advisory Committee (PBAC) are confidential, the research team may not have had access to all relevant evidence. We would welcome access to such information from which to prepare revised estimates. Placing all submissions to the PBAC in the public domain, as now occurs with reports of the PBAC, would allow a more informed public debate on these matters and would be most welcome.

Leonie Segal · Richard H Osborne · Susan E Day

The Australia–United States Free Trade Agreement (AUSFTA) contains major concessions to the US pharmaceutical industry that may undermine the egalitarian principles and operation of the Pharmaceutical Benefits Scheme (PBS) and substantially increase the costs of medicinal drugs to Australian consumers. AUSFTA’s approach to the PBS excessively emphasises the need to reward manufacturers of “innovative” new pharmaceuticals, instead of emphasising consumers’ need for equitable and ...

Ken J Harvey MB BS, FRCPA · Thomas A Faunce LLB(Hons), BMed, PhD · Buddhima Lokuge MB BS, MPH · Peter Drahos GDLP, LLM, PhD

There have been major advances in clinical understanding and treatment of bipolar disorder over the past decade. Randomised controlled trials of pharmacological treatments and psychological interventions have shown that there are effective short-term and long-term treatments for the disorder. Despite advances in treatment, diagnosis is often delayed or mistaken, and many people who could benefit are not using the treatments available. Functional and symptomatic recovery from episodes of bipolar disorder is frequently less complete than previously considered, and disability is often profound. Although manic episodes are the distinguishing feature of bipolar disorder, it appears that depression is the predominant mood disturbance and that much of the functional impairment associated with bipolar disorder results from this. Comorbidity with anxiety disorders or substance misuse is common. Advances in genetics, brain imaging and basic pharmacology are starting to provide understanding of the complex causative processes.

Philip B Mitchell MD, FRANZCP, FRCPsych · Gin S Malhi MB ChB, FRANZCP, FRCPsych · Jillian R Ball BA, MA (ClinPsych), PhD

Most consumers consider complementary and alternative medicine (CAM) products inherently safe. The growing simultaneous use of CAM products and pharmaceutical drugs by Australian consumers increases the risk of CAM–drug interactions. The Therapeutic Goods Administration (TGA) has a two-tier, risk-based regulatory system for therapeutic goods — CAM products are regulated as low risk products and are assessed for quality and safety; and sponsors of products must hold the evidence for any claim of efficacy made about them. Adverse reactions to CAM products can be classified as intrinsic (innate to the product), or extrinsic (where the risk is not related to the product itself, but results from the failure of good manufacturing practice). Adverse reactions to CAM practices can be classified as risks of commission (which includes removal of medical therapy) and risks of omission (which includes failure to refer when appropriate). While few systematic studies of adverse events with CAM exist, and under-reporting is likely, most CAM products and practices do not appear to present a high risk; their safety needs to be put into the perspective of wider safety issues. A priority for research is to rigorously define the risks associated with both CAM products and practices so that their potential impact on public health can be assessed.

Stephen P Myers PhD, BMed, ND · Phillip A Cheras PhD, BAppSc

Michael C Kennedy Research Associate, Department of Clinical Pharmacology and Toxicology, St Vincent’s Hospital, Darlinghurst, NSW 2010. drmkennATozemail.com.au To the Editor: Since the Sydney Olympics in 2000, many developments have occurred in drug use and the rules regulating drugs in sport. The most significant regulatory development is the acceptance by the Olympic Federation, and many other sports bodies, of the World Anti-Drug Agency’s World Anti-Doping Code.1 Caffeine and pseudoephedrine have been removed from the Prohibited List, and an in-competition monitoring program is under way to detect any changes in the patterns of use of caffeine, pseudoephedrine and other drugs not on the banned list. Had this code been used in 2000, the Romanian gymnast Andreea Raducan would have retained her gold medal, lost after she inadvertently used a cold preparation containing pseudoephedrine. Precise in-competition limits on blood and breath alcohol have been introduced in sports such as archery and modern pentathlon. β-Blocking agents and diuretics are completely banned in specific sports. A new category of “specified substances” now exists: . . . the prohibited list may identify specified substances which are particularly susceptible to unintentional anti-doping rule violations because of their general availability in medicinal products or which are less likely to be successfully abused as doping agents. These substances include cannabinoids, probenecid, glucocorticosteroids and ephedrine. Doctors treating athletes should advise them to inform their relevant sporting authority of drugs prescribed. If necessary, athletes can apply to the Australian Sports Drug Advisory Committee for a therapeutic use exemption for a banned substance. Notifiable substances can be documented on an Abbreviated Therapeutic Use Exemption form held by the national sporting body. There can be no doubt of the need for drug testing to ensure a level playing field. Drug use to enhance performance is unabated since the Sydney games, with scandals occurring around the world. The Bay Area Laboratory Corporation scandal, involving the anabolic steroid tetrahydrogestrinone, is the most prominent. This has ruined several sporting careers and led to criminal charges against company directors.2 Other anabolic steroids continue to be widely used, including nandrolone, which causes problems because of contamination of dietary supplements and some foods.3 One of the “holy grails” for drug cheats over the past 4 years has been to enhance oxygen transport and delivery. RSR13 (efaproxiral), an allosteric modifier of haemoglobin, is in clinical trial as a radiosensitising agent. It has been shown to increase Vo2max in dogs and hence has been of interest to endurance athletes. The manufacturer’s collaboration with the Olympic Analytical Laboratory of the University of California (Los Angeles) resulted in an analytical method now being available for detection of the drug in sport.4 Haemoglobin- and non-haemoglobin-based oxygen carriers are now available commercially. There are few scientific data about their use in sport, but it is likely they are misused by some athletes.5 Recombinant human erythropoietin is widely used in cycling and other endurance sports. A detection method developed from Australian research will limit its use, at least at the Olympic venue.6 Genetic manipulation is unlikely in 2004, but its potential is foreseen. This technology is also prohibited in the new code.1 Unfortunately, drugs will continue to be misused. The opportunity for Olympic winners to gain huge financial rewards will fuel their use.

Michael C Kennedy

James D Kidd Retired General Practitioner, The Medical Centre, 125 River Road, Emu Plains, NSW 2750. To the Editor: Although I am retired, I wish to make some comment on the controversy about the use of ciprofloxacin in the treatment of chronic suppurative otitis media.1 I still feel uneasy when there is mention of the topical use of an antibiotic that may be used either orally or parenterally. Many years ago, when I had a large practice, including paediatric patients, chronic suppurative otitis media was common, although most cases responded to the classical ear drops. However, some persisted and, not infrequently, a new patient would present with this problem. As mentioned, most were the result of a pseudomonas infection. Pseudomonas was then a common problem in chronic leg ulcer of the elderly, and I had found that treatment with Burrow’s solution (aluminium sulfate [2.25 g], acetic acid [33%], tartaric acid [0.45 g], calcium carbonate [1 g], purified water [7.5 mL]) was very successful and continued to be successful right up to my retirement, even in new cases which had been treated unsuccessfully with ciprofloxacin. Before the advent of ciprofloxacin, I used Burrow’s solution ear drops in many adult cases of chronic suppurative otitis media with great success. As the number of children with this problem grew, I attempted to get advice on the use and any toxicity of Burrow’s solution ear drops in children. I could not find anyone at the Children’s Hospital with any experience, but the consensus was that it was unlikely to be toxic. Although at first I had difficulty in getting the chemist to make up ear drops for adults, by this time there was little problem getting them made for children, and the results were dramatic. There were recurrences, but these responded as well as they did the first time they were treated. Advice on correct aural hygiene after swimming and bathing was important. Burrow’s solution kills pseudomonas. Am I too old fashioned?

James D Kidd

A complementary and alternative medicine (CAM) system divorced from scientific medicine means that patients can only benefit from the best of both systems by dividing their care. Science must be used to stimulate convergence of complementary and traditional healthcare. First class research to examine the more interesting claims of the alternative health industry is essential to broaden the range of therapeutic options available, while minimising fraudulent, ill-informed and sometimes dangerous practices. Mutual respect and interest between orthodox and alternative practitioners is appropriate, but there can be no compromise involving unscientific approaches to care. Health departments must play a greater role in stopping fraudulent claims being publicised, and in warning consumers about such claims.

John M Dwyer AO, FRACP, PhD

Randomised trials suggest that ximelagatran is “non-inferior” to warfarin for preventing stroke in patients with non-valvular atrial fibrillation, but important questions remain Atrial fibrillation is a strong and independent risk factor for stroke because it predisposes to thrombus formation in the left atrial appendage, and subsequent embolism to the brain.1 Each year, at least 6000 cardioembolic ischaemic strokes occur among an estimated 150 000 Australians with atrial fibrillation,2,3 and these numbers are expected to rise substantially with the ageing of the Australian population and associated increase in the prevalence of atrial fibrillation. The only two treatments proven to reduce the risk of stroke among patients with atrial fibrillation are aspirin and adjusted-dose warfarin.4 However, both have limitations. Aspirin is only modestly effective, reducing the risk of stroke by about a fifth compared with placebo (absolute risk reduction [ARR], 1.7% per year; number of patients needed to treat for one year to prevent one stroke [NNT], 59). Warfarin reduces the risk of stroke by about two-thirds compared with placebo (ARR, 3.1% per year; NNT, 32) and by about a third compared with aspirin (ARR, 0.8% per year; NNT, 125), but causes at least twice as many intracranial and extracranial bleeds as aspirin, particularly in patients at increased risk of bleeding (eg, those aged over 75 years, those with a history of bleeding; see Box 1).4 Warfarin is also inconvenient to use because it has a narrow therapeutic index, interacts with numerous drugs and food, and requires close laboratory monitoring (Box 2).5 Consequently, only a third to a half of patients with atrial fibrillation who are appropriate candidates for warfarin therapy actually receive it.6 Reducing the intensity of warfarin therapy to an international normalised ratio (INR) of less than 2.0 lowers the risk of bleeding, but is associated with an increased incidence of ischaemic stroke and worse stroke outcomes compared with standard-intensity warfarin therapy (INR ≥ 2.0).7 Direct thrombin inhibitors are a new class of anticoagulant drugs that bind directly to thrombin and block its interaction with substrates, thus inhibiting fibrin formation, thrombin-mediated activation of coagulation, and thrombin-induced platelet aggregation. Hirudin is the only direct thrombin inhibitor currently available for use in Australia, but must be given parenterally and is approved only for the treatment of heparin-induced thrombocytopenia. Ximelagatran, a pro-drug of melagatran, is an orally administered direct thrombin inhibitor and the newest drug in this class. It is rapidly absorbed from the gut and converted to its active form, melagatran. Melagatran is not metabolised or bound to plasma proteins. It is cleared predominantly (about 80%) by the kidneys, and has a half-life of 4–5 hours, which means ximelagatran needs to be administered twice daily (Box 2). Two large phase III randomised trials have recently evaluated ximelagatran as a replacement for warfarin to prevent thrombotic complications in patients with non-valvular atrial fibrillation.8,9 The primary objective of the Stroke Prevention using the ORal direct Thrombin Inhibitor ximelagatran in patients with non-valvular atrial Fibrillation (SPORTIF) III and V trials was to determine whether ximelagatran given in a fixed dose of 36 mg twice daily without laboratory monitoring was non-inferior to adjusted-dose warfarin (INR, 2.0–3.0) for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation and at least one additional major risk factor for stroke. The prespecified criterion for non-inferiority required that the lower confidence interval for the difference in the rate of stroke or systemic embolism between ximelagatran and warfarin did not exceed the prespecified threshold of 2% per year.10 Establishment of non-inferiority would imply that ximelagatran has either equivalent or superior effectiveness to warfarin and would allow clinicians to select ximelagatran over warfarin for convenience or safety. The design of the two SPORTIF trials was identical, except that SPORTIF III (3407 patients) was conducted in Europe, Asia, Australia and New Zealand and treatment allocation was open label, while SPORTIF V (3922 patients) was conducted in North America and treatment allocation was double blinded. The pooled results of the SPORTIF III and V trials (which had mean follow-up periods of 17 or 20 months, respectively) showed no significant difference in the risk of stroke or systemic embolism between ximelagatran (2.5%) and warfarin (2.5%; Box 1). In both trials, findings for ximelagatran fulfilled the criterion for non-inferiority. However, the pooled results of the SPORTIF trials also showed that ximelagatran significantly reduced the risk of major bleeding compared with warfarin (2.5% for ximelagatran; 3.4% for warfarin; estimated annualised ARR, 0.6%; NNT for 1 year to avoid one major bleed, 167) and increased the risk of transiently elevated levels of liver alanine aminotransferase (ALT) enzymes (6.1% for ximelagatran; 0.8% for warfarin; absolute risk increase [ARI], 5.3%; number of patients needed to treat with ximelagatran to harm [NNH] with increased ALT, 19). Raised ALT levels typically occurred 2–6 months after initiation of ximelagatran therapy, but produced no symptoms, were transient (returning to baseline spontaneously or after cessation of treatment), and without sequelae in all cases reported in the SPORTIF trials. These results suggest the beginning of the end of warfarin, because ximelagatran is not only associated with less major bleeding than warfarin, but it also has a predictable pharmacokinetic profile (uninfluenced by the patient’s age, sex, weight, ethnicity or diet). Therefore, it is not necessary to monitor anticoagulation activity or adjust the dose of ximelagatran (except in patients with renal dysfunction, in whom a decrease in dose or longer dosing interval is likely to be required). Furthermore, ximelagatran has a wider therapeutic margin than warfarin, and a low potential for drug interactions (Box 2). Although the cost of ximelagatran is likely to be substantially higher than the cost of warfarin, it may prove to be more cost effective because of its lower risk of bleeding and superior convenience (eg, no laboratory monitoring). Yet, important questions remain. First, there was significant heterogeneity between the two SPORTIF trials (P = 0.02). In the SPORTIF III trial, random allocation to open-label ximelagatran was associated with an absolute reduction in stroke or systemic embolism of 0.7% per year compared with warfarin, whereas in the SPORTIF V trial allocation to double-blinded ximelagatran was associated with an absolute increase in stroke or systemic embolism of 0.4% per year compared with warfarin. The cause of this heterogeneity remains uncertain, but might, at least in part, be accounted for by diagnostic suspicion or reporting bias in the open-label SPORTIF III trial. Second, the 2% per year threshold that was chosen as the criterion for non-inferiority does not reliably exclude even a near doubling of risk of stroke or systemic embolism with ximelagatran compared with warfarin. Third, unexpected hepatic side-effects of ximelagatran are an important concern given their high incidence in the short-term (6%), the large population potentially eligible for ximelagatran, and the likely long-term exposures to ximelagatran (and possibility of other long-term adverse effects). Monitoring of liver function is likely to be required during the first 6 months of treatment, and additional long term outcome data are required. The SPORTIF data signal the emergence of ximelagatran as an effective, safe and more convenient long-term alternative to warfarin for preventing stroke in patients with non-valvular atrial fibrillation. Safety concerns and cost issues are likely to delay its approval and eventual uptake by clinicians in Australia. In the meantime a range of other new antithrombotic drugs are also being evaluated for this indication. Both idraparinux (a selective clotting factor Xa inhibitor administered by once-weekly subcutaneous injection) and the combination of aspirin and clopidogrel are being tested in clinical trials, and novel oral preparations of direct-thrombin inhibitor and factor Xa inhibitors are in clinical development. This is heartening news for patients with atrial fibrillation, their doctors, and also public health professionals and governments faced with a looming epidemic of morbidity caused by atrial fibrillation in the ageing Australian community. 1: Estimated benefits and risks of treating a typical cohort of 1000 patients with non-valvular atrial fibrillation with aspirin, adjusted-dose warfarin, or ximelagatran* Aspirin (v placebo) Warfarin (v placebo) Warfarin (v aspirin) Ximelagatran (v warfarin)† Stroke‡ ARR ↓ 17 NNT 59 ARR ↓ 31 NNT 32 ARR ↓ 8 NNT 125 ARR§ 0 NNT§ — Major extracranial bleeds¶ ARI ↑ 1 NNH 1000 ARI ↑ 3 NNH 333 ARI ↑ 2 NNH 500 ARR ↓ 6 NNT 167 ALT ≥ 3 times upper limit of normal — — — — — — ARI ↑ 53 NNH 19 ARR =absolute risk reduction. ARI = absolute risk increase. NNT = number of patients needed to treat for one year to prevent or avoid one event. NNH = number of patients needed to treat for one year to harm by causing one event. ALT = alanine aminotransferase. * Data for aspirin v placebo, warfarin v placebo, and warfarin v aspirin are adapted from Hart et al.4 † ARR and NNT in the SPORTIF trials were calculated by dividing the pooled event rate by the mean duration of follow-up in years (approximately 1.5 years). ‡ Includes haemorrhagic stroke. § Includes stroke and systemic embolism. ¶ Event rates are likely to be substantially higher outside clinical trial settings, in the elderly, and in those with major comorbid conditions. 2: Comparison of the pharmacology and costs of aspirin, adjusted-dose warfarin and ximelagatran to prevent stroke in patients with non-valvular atrial fibrillation Aspirin Warfarin Ximelagatran Route Oral Oral Oral Dose 150–325 mg Variable* 36 mg Frequency Once daily Once daily Twice daily Half-life 20 minutes 40 hours 4–5 hours Clearance Systemic Hepatic Renal† Laboratory monitoring Not required INR Liver function tests‡ Antidote No Yes — Vitamin K No Reversal of antithrombotic effect Platelet transfusion Vitamin K Fresh frozen plasma Prothrombinex Discontinue ximelagatran Maintain diuresis Haemodialysis Food interactions Nil Multiple Nil known Drug interactions Uncommon Multiple Nil known Major side-effects Gastrointestinal bleeding Bleeding Bleeding Abnormal liver function test results Precautions and contraindications Bleeding diathesis Peptic ulcer Allergy Bleeding diathesis Alcoholism Dementia Impaired liver function Bleeding diathesis Impaired renal function Impaired liver function Approximate costs $2 per month§ $10 per month§ Unknown¶ INR = international normalised ratio. * Dose adjusted according to the results of the INR. † Trials of ximelagatran in atrial fibrillation have been restricted to patients with a creatinine clearance rate of ≥ 30 mL/min. ‡ Monitoring of liver function is likely to be required for the first 6 months. § Pharmaceutical Benefits Scheme November 2003: aspirin, $6.13 for 112 100 mg enteric-coated tablets; warfarin, $8.40 for 50 5 mg tablets (does not include the cost of laboratory monitoring). ¶ Cost of ximelagatran is not known but is likely to be at least $100 per month for a private prescription.

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

The impact of a computer-based infectious diseases electronic antibiotic advice and approval system (“IDEA3S”) was assessed as an alternative to a labour-intensive, phone-based approval system. IDEA3S-based approvals replaced 48% of all approvals for the most frequently requested antimicrobial agents (ceftriaxone/cefotaxime, vancomycin) and were associated with stable overall rates of antimicrobial use. Antibiotic prescribing for community-acquired pneumonia was 76% concordant with IDEA3S recommendations, and clinical acceptance of IDEA3S was excellent. Successful implementation required a coordinated, evidence-based approach between clinicians, pharmacists and hospital administration, together with ongoing staff education and feedback of results. IDEA3S is a useful new adjunct to routine clinician consultation to support appropriate antibiotic prescribing for a number of common indications in hospitals.

M Lindsay Grayson MD, FRACP, FAFPHM · Sharmila Melvani BPharm · Sue W Kirsa BPharm, GradDipHospPharm · Stephen Cheung BPharm, GradDipInfoSys · M Kent Garrett BPharm, GradDipHospPharm · Anthony M Korman MB BS, FRACP · William A Thomson BPharm, MSc, FSHPA

John Coutsouvelis,* Carmela E Corallo† * Oncology Pharmacist, † Deputy Director of Pharmacy, Box Hill Hospital, Nelson Road, Box Hill, VIC 3128. John.coutsouvelisATboxhill.org.au To the Editor: Thalidomide has recently been approved for use in treating recurrence of erythema nodosum leprosum and multiple myeloma after failure of standard therapies. Common side effects of thalidomide treatment include drowsiness, sedation, rash and paraesthesiae.1 Dizziness, hypotension and bradycardia occur less commonly.1-3 Of 91 patients treated with thalidomide (80 with multiple myeloma), we have had one case of symptomatic bradycardia. We describe this patient, who was able to continue treatment on a reduced dose of thalidomide. A 71-year-old woman, with a history of breast cancer (treated with radiotherapy and tamoxifen), arthritis, crush fractures, and hip and knee replacement, was diagnosed with multiple myeloma. She was prescribed intravenous pamidronate 90 mg every month and oral therapy with melphalan, but she experienced haematological toxicity and the melphalan was stopped. After progression of the disease, 100 mg of thalidomide was commenced at night, with the aim of increasing the dose by 100 mg every fortnight until a response was achieved. Three weeks later, the patient presented to hospital for pamidronate infusion complaining of a 2-week history of shortness of breath, especially on exertion. There was no oedema present, and her blood pressure was 135/70 mmHg. Electrocardiography showed sinus bradycardia, with a heart rate of 46 beats/min. The dose of thalidomide had been titrated to 200 mg at night. Thalidomide was stopped, and the patient was referred to a cardiologist, who performed an echocardiogram, 24-hour Holter monitoring and a stress test. The results from these tests showed no underlying cardiac disease or abnormalities. Six weeks later, on review, the bradycardia had resolved (heart rate, 60 beats/min). Thalidomide was recommenced at 100 mg daily. However, after a further 6 weeks, her heart rate had decreased again to 45 beats/min, and the dose of thalidomide was reduced to 100 mg on alternate days. Thalidomide therapy has been continued in this patient at 100 mg on alternate days. Her heart rate has stabilised between 50 and 55 beats/min, and she has remained asymptomatic. The multiple myeloma is responding to treatment, as indicated by symptom control and serial measurements of IgG kappa. She continues to take hydroxychloroquine, rofecoxib and sertraline. Bradycardia is a rare side effect of thalidomide therapy, with an incidence of 0.12%.1,2 The mechanism is unknown, but could be related to thalidomide’s central sedative effect.1 There are isolated published case reports of thalidomide-induced bradycardia; in all cases the drug was stopped.2-5 Thalidomide is being used for various conditions for which no alternative therapy exists. As the drug is now commercially available in Australia, its use is likely to increase. In all patients taking thalidomide, we recommend measuring heart rate; and in those with underlying heart disease, or who are taking medications that can precipitate bradycardia, we recommend electrocardiographic monitoring. Our findings in this patient suggest that thalidomide-induced bradycardia can be successfully managed with dose reduction and regular monitoring.

John Coutsouvelis · Carmela E Corallo

Timothy H J Florin Director of Gastroenterology, Department of Medicine, University of Queensland, Mater Health Services’ Adult Hospital, South Brisbane, QLD 4101. t.florinATuq.edu.au To the Editor: In their article on adoption of celecoxib and rofecoxib by Australian general practitioners, Kerr et al noted that “the increase in COX-2 [cyclooxygenase-2] prescribing coincided with a period of energetic marketing to the medical profession, which promoted the message that the new C2SNs [COX-2-selective non-steroidal anti-inflammatory drugs] were ‘safer’ than traditional NSAIDs [non-steroidal anti-inflammatory drugs].”1 The implication is that the decision of Australian GPs to prescribe these new drugs may have been less than independent or rationally informed. The reason for prescribing C2SNs is that, like traditional NSAIDs, they relieve arthritic pain and so promote mobility, although, unlike traditional NSAIDs, they do not inhibit cyclooxygenase-1. While the power of advertising is undeniable, the simple message about C2SNs is that there is an approximate 50% reduction in clinically significant gastrointestinal (GI) complications compared with traditional NSAIDs.2 There are over a dozen articles to support the better GI side-effect profile of C2SNs. Most data support a non-cumulative, reversible, but constant, risk of peptic and other, more distal GI bleeds, or perforation, with the coefficient of risk being significantly greater for NSAIDs.3 Although the data from the CLASS study did suggest that the higher GI morbidity of NSAIDs seemed to diminish with time,4 that of celecoxib remained at a constantly lower rate.5 This is clinically important for all our patients, and especially for our ageing population with their comorbid conditions and polypharmacy. I suggest that it is for this single reason that many doctors have been quick to take up C2SNs for their patients. The better GI safety enfranchised patients who previously could not take NSAIDs safely, and could explain why the overall anti-inflammatory market increased by 20%.1 However, no one suggests that the C2SNs are free of non-GI side-effects. To the best of my knowledge, COX-2-specific NSAIDs have not been promoted as being free of non-GI side-effects or better than COX-1-specific NSAIDs in this regard. While agreeing with the last sentence of Dowden’s editorial that “new is not always better”,3 the opposite — that “new is sometimes better” — is also true. Thus, we persuaded the accountants in our hospital, who rightly participate in the determination of which drugs are available on its formulary, to accept one of the COX-2 drugs because of its better GI complication profile. While this will not reduce its pharmacy budget, it is anticipated to reduce overall hospital costs in this area,5 which should allow a reapportionment of its budget to other areas of need. Of course, the hospital is watching carefully for any unforeseen “serious adverse effects which sometimes only emerge after marketing”.3

Timothy H J Florin

Stephen J Kerr,* Andrea Mant,† Fiona E Horn,‡ Kevin McGeechan,§ Geoffrey P Sayer¶ * Decision Support Coordinator, National Prescribing Service, PO Box 1147, Strawberry Hills, NSW 2012; † Area Advisor, Quality Use of Medicines, South East Health, Sydney Hospital, Sydney, NSW; ‡ Research Analyst, § Senior Research Analyst, ¶ General Manager — Research, Health Communication Network, St Leonards, NSW. skerrATnps.org.au In reply: The advantage of the COX-2-selective NSAIDs (C2SNs) is the reduction in clinically significant gastrointestinal complications compared with conventional NSAIDs, but, as Florin agrees, other toxicities, including the risk of renal failure and heart failure, are similar for C2SNs and the older drugs.1 We speculated that doctors may have been more aware of the differences between the new and the conventional anti-inflammatories rather than the similarities: between 4.7% and 7.9% of patients in our study cohorts were treated with a combination of drugs which placed the patient at risk of renal complications. Florin points out that there is an approximate 50% reduction in clinically significant gastrointestinal (GI) complications with C2SNs compared with conventional NSAIDs. If, in a population, the annual incidence of serious GI complications with NSAID use is around 1.4%,2 then the absolute risk reduction is 0.7%. This means that about 140 patients would need to be treated with a C2SN for one year to prevent one serious GI complication. Messages conveyed in this way may be more pertinent to clinical decision making than a statement about relative risk reduction. Florin also notes the problems with elderly patients who often take multiple medications, and are probably at increased risk of upper-GI events with NSAIDs. Our data demonstrated very high prescribing rates in patients who were not elderly. Over 20% of patients in our cohorts were aged less than 50 years, and over 50% were aged less than 65 years. Furthermore, between 34.5% and 61.3% had no pain medication prescribed in the 12 months before the first C2SN prescription, suggesting that C2SNs may have been used as a first-line pain medication in these patients. Quality use of medicines advocates prescribing which is safe, judicious, effective and cost-effective. Recent pharmacoeconomic studies suggest the cost-effectiveness may only be realised when prescribing of C2SNs is confined to patients who are at high risk of GI complications.3,4

Stephen J Kerr · Andrea Mant · Fiona E Horn · Kevin McGeechan · Geoffrey P Sayer

John S Dowden Editor in Chief, Australian Prescriber, Suite 3/2 Phipps Close, Deakin, ACT 2600. jdowdenATnps.org.au In reply: The general practitioners’ decision to prescribe COX-2 inhibitors was rational, but the information underpinning their decision was less than independent. A big reduction in short-term relative risk can be persuasive, even if the absolute benefit is small. General practitioners deal with whole patients, so they consider the overall risks of treatment, and not just one adverse effect. While COX-2 inhibitors may have gastrointestinal advantages, they may have cardiovascular disadvantages. Treatments for chronic conditions should be based on long-term data. The observation that most of the ulcer complications in the second half of the CLASS study were in patients taking celecoxib is therefore important.1 Undoubtedly, some patients who could not take non-selective non-steroidal anti-inflammatory drugs (NSAIDs) were able to tolerate COX-2 inhibitors. However, Kerr et al found that up to 61% of patients given a COX-2 inhibitor had not previously been prescribed any analgesia.2 It seems unlikely that so many people suddenly required analgesia that only a COX-2 inhibitor could provide. The Pfizer-funded study by MacDonald et al shows that UK general practitioners tended to prescribe COX-2 inhibitors for patients at risk of gastrointestinal haemorrhage.3 This follows the advice of the National Institute of Clinical Excellence (NICE). However, NICE also recommended against the routine use of COX-2 inhibitors.4 A review by the Canadian Co-ordinating Office for Health Technology Assessment has also concluded that COX-2 inhibitors may have no significant safety advantage over diclofenac.5 Solomon et al conclude that the cost of adverse effects of NSAIDs in low-risk elderly patients is modest.6 However, there is no comparison with COX-2 inhibitors, so we do not know if they reduce this cost. Hospital accountants may be interested to know that researchers at the Mayo Clinic concluded that, in terms of averting gastrointestinal events, the most cost-effective analgesic is paracetamol.7

John S Dowden

The comparison of disparate interventions for the prevention and management of osteoarthritis (OA) is limited by the quality and quantity of published efficacy studies and the use of disparate measures for reporting clinical trial outcomes. The “transfer to utility” technique was used to translate published trial outcomes into a health-related quality-of-life (utility) scale, creating a common metric which supported comparisons between disparate interventions. ...

Leonie Segal MEcon, PhD · Susan E Day BA, MA · Adam B Chapman BA/BSc(Hons), MPH · Richard H Osborne PhD