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Measure of effect is not transferable
- Shalini Kapoor (22 December 2006)
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Evaluating the effects of prophylatic antibiotics in measles: a 70-year saga
- Iain Chalmers (7 January 2007)
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Re: Measure of effect is not transferable
- May-Lill Garly, Jens Nielsen, Peter Aaby (30 January 2007)
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Choice of antibiotic for prophylaxis.
- John R GILBERT (13 March 2007)
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Re: Choice of antibiotic for prophylaxis.
- May-Lill Garly, Peter Aaby (20 March 2007)
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Shalini Kapoor, SpR Leicester
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Dear Sir Measure of effect is not transferable The study by Garly et al has important methodological flaws. The measure of effect that was reported was the odds ratio of development of low respiratory complications. This is an unusual measure for a randomised controlled trial, where the relative risk and absolute risk reduction are more appropriate. It might be understandable that odds ratio was chosen over relative risk or absolute risk reduction because the study only achieved 38% of the planned sample size [84/218]. The study then went on to report the ‘Number Needed to Treat’. This requires the absolute risk reduction. This mix of the weaker odds ratio and NNT is curious. Would the results be different if the relative risk was reported? In addition the 95% confidence interval around the odds ratio of the primary outcome was reported as ‘odds ratio 0.08 (95% confidence interval 0 to 0.56). This result is clearly not possible because a ratio cannot be zero. When there is no difference between a numerator and denominator, the ratio is 1. The authors acknowledge the final sample size as a serious limitation to their study. Assuming that the null hypothesis (that there was no difference in the outcome of lower respiratory infection with antibiotics or placebo) was the basis of this study, the conclusion that prophylactic antibiotics may have an important role in the management of measles infection in low income countries is unsupported by the 38% sample size and the faulty confidence interval. Further studies are required before this paper is taken seriously. Competing interests: None declared |
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Iain Chalmers, Editor, James Lind Library James Lind Initiative
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The first controlled trial of prophylactic antibiotics in measles was sponsored by the Medical Research Council and reported in the BMJ nearly 70 years ago (2). Over the subsequent three decades, five additional controlled trials were conducted. They provided encouraging evidence that prophylactic antibiotics might achieve an important reduction in pneumonia and other complications of measles. However, no further controlled trials were done during the subsequent 30 years (2). At meeting convened by WHO in 1993 to decide on research priorities for the treatment of measles, highest priority was accorded to additional controlled trials of prophylactic antibiotics (3). The contuinuing uncertainty about the value of prophylactic antibiotics was made clear four years later in a systematic review published in the BMJ (4). It is against this background of failure by the research community to address an important uncertainty which has existed for nearly 70 years that May-Lill Garly and her colleagues must be thanked for completing an helpful study in very difficult circumstances (5). In his accompanying editorial, Neal Halsey identifies as a limitation of the trial that the authors did not mention vitamin A therapy (6). However, he might also have observed that, had researchers evaluating the effects of vitamin A in measles used factorial designs to assess the effects of vitamin A and prophylactic antibiotics separately and together, we would all have been better informed years ago about the effects of prophylactic antibiotics. References 1. Anderson T. Sulphanilamide in the treatment of measles. BMJ 1939;1:716-718. 2. Chalmers I. Why we need to know whether prophylactic antibiotics can reduce measles-related morbidity. Pediatrics 2002;109:312-315. 3. World Health Organisation. Clinical research treatment of measles: report of a meeting. Geneva: WHO 1995. WHO/CDR/95.15. 4. Shann F. Meta-analysis of rials of prophylactic antibiotics for children with measles: inadeqaute evideince. BMJ 1997;314:334-336. 5. May-Lill Garly, Carlitos Balé, Cesário Lourenco Martins, Hilton C Whittle, Jens Nielsen, Ida M Lisse, and Peter Aaby. Prophylactic antibiotics to prevent pneumonia and other complications after measles: community based randomised double blind placebo controlled trial in Guinea -Bissau. BMJ 2006;333:1245-7. 6. Halsey NA. Measles in developing countries. BMJ 2006;333:1234. Competing interests: None declared |
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May-Lill Garly, Researcher Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, DENMARK, Jens Nielsen, Peter Aaby
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Madam, We agree
with Dr. Kapoor that the preferable risk measure
would have been the risk ratio (RR). However, using the RR there was no
possibility of controlling for age and other confounders, because the
statistical analyses did not converge due to the limited power of the study.
Using logistic regression (odds ratios) we were able to do the appropriate
analyses. We investigated the differences between the methods by comparing
crude RRs and crude ORs and
found no major differences (Table).
Dr. Kapoor notes that the ‘Number Needed to Treat’ requires the
absolute risk reduction and that our mix of the weaker odds ratio and NNT is
curious. However, the NNT was calculated as the inverse of the rate of events (risk)
in the treatment arm minus the rate of events (risk) in the placebo arm. Thus
risk reduction was used as basis for the analysis. It is
indicated by Dr. Kapoor that our main result – ‘odds ratio
0.08 (95% confidence interval 0 to 0.56)’ - is clearly not possible because a
ratio cannot be zero. The zero in this confidence interval represents a rounded
value and should correctly have been written 0.00. Due to the 38% sample size and the
faulty confidence interval Dr. Kapoor maintains that
our conclusion is unsupported. Stopping the study due to a civil war in Competing interests: None declared |
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John R GILBERT, Family doctor Seabury Medical centre, Malahide, Co Dublin
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Not knowing the prevalent organisms causing community-acquired pneumonia or the patterns of antibiotic resistance in Guinea-Bissau, I hesitate to make any criticism of this work. But: I gave up prescribing co-trimoxazole about 20 years ago because the lack of effectiveness and the poor side effect profile made trimethoprim alone a better and cheaper choice. These days I prescribe macrolides first line for lower respiratory tract infections and would reserve co-trimoxazole for Pneumocystis Carinii Pneumonia - if I were ever to encounter it. Why was it chosen in this context? Competing interests: None declared |
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May-Lill Garly, Researcher Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, DENMARK, Peter Aaby
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Madam, We are aware of differences in antibiotic prescription patterns in different parts of the world – as pointed out by Dr. Gilbert. However, the use of co-trimoxazole against pneumonia is routine in Guinea-Bissau, and co-trimoxazole was the first line drug recommended by the WHO against community acquired pneumonia when the trial was planned – as mentioned in the paper. Indeed today, according to our best knowledge, co-trimoxazole together with amoxicillin, are the recommended drugs of choice against community acquired pneumonia – according to the Integrated Management of Childhood Illness (http://www.who.int/child-adolescent- health/New_Publications/IMCI/WHO_FCH_CAH_00.40/IMCI_Chapter_April01.doc, page 30). As discussed in the paper amoxicillin could be an alternative to co-trimoxazole as prophylactic antibiotic in measles although it is almost twice as expensive as co-trimoxazole and standard dosages are usually given three times a day – compared to two daily doses of co-trimoxazole. Competing interests: None declared |
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