(Aust Prescr2004;27:55-7)
The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. Letters are usually published together with their responses or comments in the same issue. The Committee screens out discourteous, inaccurate or libellous statements and sub-edits letters before publication. Authors are required to declare any conflicts of interest. The Committee's decision on publication is final.
Are new drugs as good as they claim to be?
Editor, – It was disappointing to read that there are still people questioning the gastrointestinal safety and cost-effectiveness of the COX-2 inhibitors (Aust Prescr 2004; 27:2-3). It is even more disappointing when this opinion is referenced to a single non-systematic, heterogenous review article (that is, evidence level 5), which misrepresents the body of evidence in two important ways.
The review claims that non-steroidal anti-inflammatory drugs (NSAIDs) have minimal benefit against which to compare their adverse events. This is based on a very selective use of analgesic data from the literature (which still showed a significant difference to placebo). An alternative view is that NSAIDs are the mainstay of therapy worldwide for the symptomatic relief of arthritis and occupy the first five top rankings for analgesics on the Oxford pain relief table because of their clinical benefits.1 This is backed by clinical trials where both COX-2 inhibitors and traditional NSAIDs showed statistically and clinically different efficacy to placebo in arthritis.2,3,4,5
The article by Wright also states that there is no evidence for reduced gastrointestinal damage from COX-2 inhibitors. He bases this opinion on a single flawed study (CLASS) that had a statistical power of about 45% (that is, less than a 50% chance of detecting any real differences).6 He neglects to mention the wealth of other data from adequately powered studies that show a significant difference in safety and tolerability between celecoxib and the non-specific NSAIDs.7, 8, 9, 10,11,12,13
If the COX-2 inhibitors did not represent a cost-effective treatment then they would not be listed on the Pharmaceutical Benefits Scheme. The Pharmaceutical Benefits Advisory Committee makes this decision based on evidence, not opinion.
Dr Simon McErlane
Medical Director
Pfizer Global Pharmaceuticals
Pfizer Australia
References
1. Oxford league table of analgesics in acute pain. http://www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html [cited 2004 May 14]
2. McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001;30:11-8.
3. Gibofsky A, Williams GW, McKenna F, Fort JG. Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebo-controlled trial. Arthritis Rheum 2003;48:3102-11.
4. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282:1921-8.
5. Weisman MH. Double-blind randomized trial of diclofenac sodium versus placebo in patients with rheumatoid arthritis. Clin Ther 1986;8:427-38.
6. Wright JM. The double-edged sword of COX-2 selective NSAIDs. CMAJ 2002;167:1131-7.
7. Singh G, Goldstein J, Bensen W, Agrawal N, Eisen G, Fort J, et al. SUCCESS-1 in osteoarthritis (OA) trial: celecoxib significantly reduces the risk of serious upper GI complications compared to NSAIDs while providing similar efficacy in 13,274 randomized patients [poster presented at EULAR; 2001 June 13-16; Prague].
8. Goldstein JL, Silverstein FE, Agrawal NM, Hubbard RC, Kaiser J, Maurath CJ, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95: 1681-90.
9. Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. Br Med J 2002;325:624.
10. Chan FK, Hung LC, Suen BY, Wu JC, Lee KC, Leung VK, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104-10.
11. Bensen WG, Zhao SZ, B, Zabinski RA, Makuch RW, Maurath CJ, et al. Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo. J Rheumatol 2000;27:1876-83.
12. McKenna F, Arguelles L, Burke T, Lefkowith J, Geis GS. Upper gastrointestinal tolerability of celecoxib compared with diclofenac in the treatment of osteoarthritis and rheumatoid arthritis. Clin Exp Rheumatol 2002;20:35-43.
13. Goldstein JL, Eisen GM, B, Pena BM, Lefkowith J, Geis GS. Dyspepsia tolerability from the patients' perspective: a comparison of celecoxib with diclofenac. Aliment Pharmacol Ther 2002;16:819-27.
Associate Professor J. Lexchin, the author of the editorial, comments:
Dr McErlane dismisses the results of the CLASS study on celecoxib by claiming that it was underpowered to find significant benefits. CLASS was funded by Pharmacia, the company that marketed celecoxib, and the corresponding author was a Pharmacia employee. Pharmacia is now owned by Pfizer. If there was a problem with the design of CLASS then Dr McErlane should look to his own house.
He criticises the article by Dr Jim Wright for ignoring seven articles showing the gastrointestinal benefits of COX-2 inhibitors. However, one was a poster presentation that was otherwise unpublished and two were published either just before or after Dr Wright's piece and would have been unavailable to him.
Dr McErlane has misread Wright's article. Wright does not say that COX-2 drugs have minimal benefits; what he does say is that the benefits need to be seen in the context of serious adverse events from these drugs. Serious adverse events include not only gastrointestinal problems but other adverse events. Wright combines all serious adverse events as reported in the CLASS study for celecoxib and for other NSAIDs and shows that there is no statistical difference in serious adverse events between celecoxib and the other NSAIDs. In other words, whatever reduction in gastrointestinal harms celecoxib produced was offset by a higher incidence of other serious adverse events.
Dr McErlane's letter provides a good lesson in why doctors should not rely solely on what companies have to say about their products.
Prescribing issues for Aboriginal people
Editor, – I read with interest the paper 'Prescribing issues for Aboriginal people' (Aust Prescr 2003;26:106-9). My research into the practice of remote area nursing shows that there are serious problems in the acquisition and use of drugs in remote Aboriginal settings. I would like to draw your attention to the initiatives taken in Queensland. Unlike the standard treatment manual referred to in the article, a 'Primary Clinical Care Manual' (3rd ed. 2003) has been developed by the Queensland Nursing Council, Royal Flying Doctor Service and Queensland Health, based on statutory regulations, for use by nurses authorised in isolated practice. Under State legislative provisions of the Health (Drugs and Poisons) Regulation 1996, a process is in place for the formal endorsement of nurses in isolated practice areas and for indigenous health workers with specific protocols clarifying their separate responsibilities in relation to drugs and drug use.
Jennifer Cramer
Registered nurse
Perth
Editor, – Over the past five years the use of ibuprofen to treat fever in children has increased dramatically at the Royal Children's Hospital, Melbourne. This is demonstrated by a seven-fold increase in the purchases of ibuprofen packs/year from 1999 to 2003 (Fig.1). Paracetamol usage and purchase has remained essentially unchanged over the same period, and there has been no significant change in the number or type of patients seen at our hospital. This continually increasing shift in practice has occurred despite the fact that there has been no change in hospital policy on the use of non-steroidal anti-inflammatory drugs. Furthermore, a monthly audit of ibuprofen use on our general paediatric ward showed that 36 of 38 prescriptions for ibuprofen also included paracetamol.
This change in practice may be a combination of three factors. Number one being aggressive marketing of ibuprofen by the drug company, second the change of ibuprofen syrup from Schedule 4 to Schedule 2 in 1998, and finally an increase in the number of British-trained doctors working in our institution. Ibuprofen is far more commonly used in Britain than Australia.
This therapeutic drift is occurring despite a lack of evidence to support it. Paracetamol has been used far more extensively worldwide than ibuprofen, so much so that the risks associated with the use of paracetamol are well known. The same cannot be said for ibuprofen use in children. Ibuprofen has no demonstrated advantages over paracetamol for the treatment of fever, nor has the combined use of these drugs been shown to be of benefit. In fact the combination may lead to an increased incidence of serious adverse effects and confusion regarding their correct dosing.1,2,3,4
Dr Sean Beggs
Senior Fellow, Clinical Pharmacology
Associate Professor Noel Cranswick
Director, Clinical Pharmacology
Thirza Titchen
Deputy Director of Pharmacy
Royal Children's Hospital
Melbourne
References
1. Walson PD, Galletta G, Chomilo F, Braden NJ, Sawyer LA, Scheinbaum ML. Comparison of multi dose ibuprofen and acetaminophen therapy in febrile children. Arch Pediatr Adolesc Med 1992;146:626-32.
2. McCullough HN. Acetaminophen and ibuprofen in the management of fever and mild to moderate pain in children. Paediatr Child Health 1998;3:246-51.
3. Mayoral CE, Marino RV, Rosenfeld W, Greensher J. Alternating antipyretics: is this an alternative? Pediatrics 2000;105:1009-12.
4. Lesko SM, O'Brien KL, Schwartz B, Vezina R, Mitchell AA. Invasive group A streptococcal infection and nonsteroidal anti-inflammatory drug use among children with primary varicella. Pediatrics 2001;107:1108-15.
Editor, – I think there is an unintentional inaccuracy in the Summary of the article 'Managing drug-induced hyponatraemia in adults' (Aust Prescr 2003;26:114-7). The first sentence of the Summary states that 'drug-induced hyponatraemia occurs in approximately 5% of outpatients...' but the source for this statement seems to be the Introduction which merely states that: 'A Melbourne laboratory found hyponatraemia in 4.8% of 326 923 samples from ambulatory patients...'.
Obviously the Melbourne sample is not representative of the whole population of ambulatory patients, or outpatients, as implied by the statement in the Summary. It is only a sample of patients who merited a blood sample being sent to the laboratory. Presumably these patients were sick enough for their general practitioner to investigate (we could call them 'sick outpatients'), and there is no account taken of all the ambulatory patients who did not have samples taken ('well outpatients'). The proportion of 'sick outpatients' who have samples sent to a laboratory is very small, surely less than 10% of the whole and probably much less than that. The problem with the statement in the Summary is that it is likely to be cited (especially when it appears in an authoritative publication like Australian Prescriber) but quoted out of context and so could mislead. It is certain, surely, that the proportion of outpatients with hyponatraemia is much less than 5%. Frankly, I'd be surprised if it was more than 0.5%.
Stuart Baker
Pharmacist
Mortlake, Vic.
Dr S. Fourlanos and Dr P. Greenberg, the authors of the article, comment:
We thank Mr Baker for drawing our attention to misinterpretation of the first sentence of the Summary.
We hope that other readers, like him, will have read in the Introduction the selection process for the patients referred to in the Summary.
We agree that the first sentence of the Summary should read: 'Hyponatraemia occurs in approximately 5% of ambulatory and 14% of admitted patients referred for blood tests by general practitioners'.
The prevalence of hyponatraemia in other non-admitted patients and in the broader community is also unknown to us.
