LETTERS

Early parenteral penicillin in meningococcal disease EDITOR, -There cannot be many general practitioners who, if asked about their worst waking nightmares, would not include the presentation of a child with early meningococcal meningitis. General practitioners would expect to encounter this once in 25 years on average, yet it will haunt them every time they see an unwell child with a fever. Similarly, there cannot be. many who are not aware of the need to give parenteral benzylpenicillin in this situation. Why then had about half of patients who had and were suspected to have the disease not been given the treatment, and how can the figures be improved?' I believe that had these questions been put to a general practitioner rather than an epidemiologist more useful answers would have been given in an editorial.2 Very rare threatening events that are difficult to deal with classically produce denial. Doctors are as subject to this phenomenon as anyone, and this combined with the random practical difficulties (sod's law decrees that the day you need it you left the bag at the surgery while you nipped out to do the extra visit) suggests that a 50% treatment rate is understandable. Further exhortation and penalty reinforce denial. The answer lies in a mixture of these with reduction of the threat by the provision of more relevant information (about the management of sick children) from credible educators and positive feedback about the results of efforts. This means a joint effort by paediatricians and general practitioners to understand more systematically the early management of unwell children in the community (perhaps the equivalent of the Baby Check for parents) and a confidential inquiry system for serious morbidity and mortality in children. M D STEVENSON

Bootle,

Millom, Cumbria LAl9 5TH I Cartwright K, Reilly S, White D, Stuart J. Early treatment with parenteral penicillin in meningococcal disease. BMJ 1992;305: 143-7. (18 July.) 2 Begg N. Reducing mortality from meningococcal disease. BMJ

1992;305:133-4. (18 July.)

EDITOR,-I'll continue to carry benzylpenicillin in my bag to treat suspected meningococcal infections before transfer to hospital, but I was not convinced that the studies by Strang and Pugh' and Cartwright and colleagues2 provided evidence for the efficacy of this policy. The bias introduced by the uncontrolled and non-randomised allocation of treatment in the patients they investigated would render a statistically significant result suspect. As it is, chance is the probable explanation of the results of both studies. Neither achieved a statistically significant result and the confidence limits for the mortality data in

Cartwright's study (0-2 to 1 5) are compatible with anything between an 80% decrease and a 50% increase in mortality attributable to treatment by general practitioners. If the authors truly believe that these findings are clinically important when the statistics indicate otherwise, then they need to explain the apparently great difference in quality of hospital care between Darlington (case fatality rate for patients pretreated by their general practitioners=0% (0/13)) and the southwest of England (case fatality rate= 5% (5/95)). TIM LANCASTER Manor Surgery, Oxford 1 Strang JR, Pugh EJ. Meningococcal infections: reducing the case fatality rate by giving penicillin before admission to hospital. BMJ 1992;305:141-3. (18 July.) 2 Cartwright K, Reilly S, White D, Stuart J. Early treatment with parenteral penicillin in meningococcal disease. BMJ 1992;305: 143-7. (18 July.)

EDITOR,-Jeffrie Strang and Edwin J Pugh's conclusion that parenteral penicillin given before admission probably contributed to a reduction in mortality in patients with meningococcal disease is not justified, given their short sentence that "All patients given oral antibiotics survived."' The study also failed to show a significant superiority of antibiotic treatment before admission to hospital over no antibiotic at that stage. Keith Cartwright and colleagues similarly acknowledge failure to show a significant reduction in mortality from using antibiotics before admission either in their study or in anyone else's.2 Why then are we encouraged to give an injection ofantibiotics before admitting a patient to hospital, even though it significantly reduces microbiological confirmation? I suggest that any improvement has more to do with better diagnosis than with where the patient was when first given antibiotics. If the illness is identified in the community (for example, by recognition of the rash) antibiotic treatment might be started then, but more important may be arranging rapid admission and alerting the hospital to the possible diagnosis. The higher mortality in infants and adults may be accounted for by the increasing difficulty of diagnosis with the reduced incidence of the rash in these age groups. Though I do not decry the exhortation to give parenteral antibiotics before admission to hospital when meningococcal disease is considered, the real plea must be to continue to suspect meningitis in any person who seems more ill than a simple cold might justify whether he or she has a haemorrhagic rash or not.

our hospital had received benzylpenicillin before admission. We therefore undertook a questionnaire survey of the 110 general practitioners in our district to ascertain their views on the practicability of implementing recommendations of the Department of Health and Social Security regarding giving benzylpenicillin in all cases of suspected meningococcal disease.4 Sixty six (60%) of the general practitioners responded to our questionnaire. Sixty were aware of the Department of Health's recommendations, but two thought that intramuscular instead of intravenous penicillin was recommended. Four respondents stated that they were not aware of the recommendations. Interestingly, 55 of the respondents carried benzylpenicillin in their emergency bags. Difficulty in obtaining benzylpenicillin, the possibility of it deteriorating, and the expense of stocking it were the commonly stated reasons for not carrying it. Uncertainty regarding the diagnosis, the small size of the district, the relative ease of sending patients to an open access paediatric department, and the delays entailed in injecting intravenous drugs in small children were some of the reasons stated for not giving benzylpenicillin. Encouragingly, all the general practitioners who responded to the questionnaire agreed to carry benzylpenicillin, particularly if they were provided with it. In consultation with the hospital paediatricians we have addressed all the points that the general practitioners raised and have reinforced the Department of Health's recommendations. We are currently arranging to provide benzylpenicillin to all the general practitioners in the district. Our survey highlights the difficulties perceived by general practitioners in implementing the Department of Health's recommendations. To improve the rate of administration of penicillin before admission these difficulties must be addressed. G GOPAL RAO C SELBY

Pathology Department, North Tyneside General Hospital, North Shields, Tyne and Wear NE29 8NH 1 Rouse AR. A survey of emergency penicillin treatment for meningitis. Communicable Disease Report 1992;2:R64-5. 2 Strang JR, Pugh EJ. Meningococcal infections: reducing the case fatality rate by giving penicillin before admission to hospital.

BMJ 1992;305:141-3. (18 July.) 3 Cartwright K, Reilly S, White D, Stuart J. Early treatment with parenteral penicillin in meningococcal disease. BMJ7 1992;305: 143-7. (18 July.) 4 Department of Health and Social Security. Meningococcal infection: meningitis and septicaemia. London: DHSS, 1988.

(PL/CMO(88)2.)

MICHAEL DAWSON

Stirchley Medical Practice, Stirchley, Telford TF3 I FB 1 Strang JR, Pugh EJ. Meningococcal infections: reducing the case fatality rate by giving penicillin before admission to

hospital. BMJ 1992;305:141-3. (18 July.)

Frequency of citation and outcome of cholesterol lowering trials

2 Cartwright K, Reilly S, White D, Stuart J. Early treatment with

parenteral penicillin in meningococcal disease. BMJ 1992;305: 143-7. (18 July.)

Priority will be given to letters that are less than 400 words long and are typed with double spacing. All authors should sign the letter. Please enclose a stamped addressed envelope for acknowledgment.

420

EDITOR, -Several studies have shown that general practitioners seldom give intravenous penicillin before referring patients with suspected meningitis to hospital. 3 In the past 30 months only two of the 16 patients with meningococcal infection treated in

EDITOR,-Meta-analysis will inevitably be biased if the data from the individual trials are biased. To avoid this it is essential to ensure that (a) only intention to treat analyses are used; (b) only trials in which participants have been properly randomised between intervention and control groups (with or without stratification) are included; and (c) cholesterol lowering is not confounded by other interventions that might offer an alternative

BMJ VOLUME 305

15 AUGUST 1992

explanation for any effects seen. It is, of course, also important to seek out data from unpublished trials to avoid potential publication bias. Ravnskov's report fails in all these respects.' Two trials did not allocate individual treatment by a randomisation procedure,23 and these cannot have ensured avoidance of non-random imbalances of variables prognostically important to outcome between the groups.4 Four trials tested multifactorial interventions, and two were not based on an intention to treat analysis.56 Avoiding analyses that are not intention to treat analyses is critically important since intention to treat analyses of the same data may generate results that are quantitatively and qualitatively different. An intention to treat analysis of each trial should be obtained or these results excluded. Four of the trials were of pharmacological doses of oestrogen in men and one of dextrothyroxine, both of which are long abandoned, and two of these trials were stopped prematurely. These interventions were confounded by cardiotoxic effects and should not be included. Ravnskov claims that there is no decrease in mortality or morbidity from coronary heart disease with cholesterol reduction; this is in contrast to results of other meta-analyses.7" The conclusions are not supported by Ravnskov's data. The author shows a significant 10% reduction in coronary morbidity but dismisses this for several reasons, including allocation to treatment groups by stratification in some trials, suggesting that such allocation implies non-randomisation. But patients were randomised after being stratified by age, sex, and other factors. The general finding has been of roughly a 20% decrease in morbidity from coronary heart disease and a 10% decrease in mortality from the disease for a 10% reduction in cholesterol concentration within a few years (R Peto, personal communication).4 Because most trials have been conducted in middle aged men at low risk of the disease there have collectively been too few deaths for the very small reductions in total mortality that would be expected from the modest effect of a 10% cholesterol reduction on coronary mortality to be reliably detected or excluded. Clear evidence of any effect of cholesterol lowering on total and noncoronary heart disease mortality will require trials with more power than those completed to date and, quite possibly, than those now being carried out. ' We believe that the balance of currently available evidence supports a policy in clinical practice of considering lipid lowering treatment for patients with hypercholesterolaemia when they are at high risk of premature coronary heart disease as the benefits of cholesterol reduction seem to be greatest in those most at risk. Unfortunately, many people who might benefit from advances in lipid lowering treatment, such as those with severe genetic hyperlipidaemias or with established coronary heart disease, are frequently undiagnosed and untreated. Let us now move the debate on to the definition and identification of groups who should receive lipid lowering treatment.

3 World Health Organisation European Collaborative Group. European collaborative trial of multifactorial prevention of coronary heart disease: final report on the 6-year results. Lancet 1986;i:869-72. 4 Chalmers TC, Celano P, Saxks HS, Smith H Jr. Bias in treatment assignment in controlled clinical trials. N Engl J Med 1983;309:1358-61. 5 Marmorston J, Moore FJ, Hopkins CE, Kuzma OT, Weiner J. Clinical studies of long term estrogen therapy in men with myocardial infarction. Proc Soc Exp Biol Med 1%2;110:400. 6 Committee of Principle Investigators. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. BrHeartj 1978;40:1069-103. 7 Holme I. An analysis of randomised trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence. Circulation 1990;82:1916-24. 8 Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction. N Engl,J .Ued 1990; 323:1112-9. 9 Peto R, Yusuf S, Collins R. Cholesterol-lowering trial results in their epidemiological context. Circulation 1985;72:451. (Abstract.) 10 Collins R, Keech A, Peto R, Sleight P, Kjekshus J, Wilhelmsen L, et al. Cholesterol and total mortality: need for larger trials. BMJ 1992;304:1689. (27 June.)

EDITOR,-It would be regrettable if U Ravnskov's paper on the frequency of citation and outcome of cholesterol lowering trials challenged confidence in the issues that are not disputable-namely, that there is a strong relation between blood cholesterol concentrations and coronary heart disease and that intervention trials that include lowering blood cholesterol concentrations show a benefit in terms of a reduction in non-fatal coronary heart disease. Furthermore, strict dietary control and a reduction in smoking in men with high cholesterol concentrations may halve the rate of fatal heart attacks.2 Ravnskov accuses the authors of papers on, and trials of, preventing coronary heart disease of selective citation, bias, and questionable veracity. But Ravnskov's paper is not free of bias: it ignores the weight of evidence that intervention including a reduction in blood cholesterol concentrations by diet and drugs limits progression and can lead to regression of atheroma.3-7

Manchester M F LAKER

Secretary, British Hyperlipidaemia Association, Department of Clinical Biochemistry, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH A KEECH Clinical Trials Servrice Unit, Oxford University, Oxford I Ravnskov U. Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ 1992;305: 15-9. (4 July.) 2 Oliver MF, Boyd GS. Influence of reduction of serum lipids on prognosis of coronary heart disease. A five-year study using oestrogen. Lancet 1961;ii:499-505.

BMJ

VOLUME

305

15

AUGUST

1992

F L GAME R H NEARY Central Pathology Laboratory, North Staffordshire Hospital Centre, Stoke on Trent ST4 7PA

J F GOODWIN Chairman, National Forum for Coronary Heart Disease Prevention, London WC I H 9TX I Ravnskov U. Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ 1992;305: 15-9. (4 July.) 2 Hjermann I, Velve Byre K, Holme I, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease: report from the Oslo study group of a randomised trial in healthy men. Lancet 198 1;ii: 1303-10. 3 Blankenhorn DH, Alaupovic P, Wickham E, Chin HP, Azen SP. Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts. Lipid and nonlipid

factors. Circulation 1990;81:470-6. 4 Davies MJ, Krikler DM, Katz D. Atherosclerosis: inhibition or regression as therapeutic possibilities. Br Heart J 1991;65: 302-10. 5 Collins P, Fox K. The pathogenesis of atheroma and the rationale for its treatment. Eur HeartJ7 1992;13:560-5. 6 Watts GF, Lewis B, Brunt JNH, Lewis ES, Coltart D], Smith LDR, et al. Effects on coronary artery disease of lipid lowering diet, or diet plus cholestyramine, in the St Thomas' atherosclerosis study (STARS). Lancet 1992;339:563-9. 7 Schuler G, Hambrecht R, Schlierf G, Grunze M, Methfessel S, Hauer K, et al. Myocardial perfusion and regression of coronary artery disease in patients on a regimen of intensive physical exercise and low fat diet. J Am Coll Cardiol 1992;19:

34-42.

P N DURRINGTON

Chairman, British Hvperlipidaemia Association, Department of Medicine, Manchester Royal Infirmary,

respectively. The numbers studied in the excluded trials were considerably lower at 13 194, accounting for only 10-3% of trial participants yet 20-3% of all deaths; this added considerable bias when Ravnskov pooled all the trials. It is unfortunate that the above data were not included in Ravnskov's subgroup analysis. Furthermore, Ravnskov excluded results from the 11 year follow up of the nicotinic acid branch of the coronary drug project, a major supportive trial,2 but included the unsupportive early results. We do not dispute the fact that frequent citation of reports tends to propagate a particular view. Twenty or so years ago, when many of the unsupportive studies were reported, however, there were fewer similar reports on lipid lowering with, consequently, a lower citation rate in the first four years after publication. Additionally, a report is more likely to cite another to support its conclusions. Indeed, this may be one reason why Ravnskov fails to mention the findings of the six studies of the regression of atheroma, none of which support Ravnskov's conclusions. The poor relation between outcome and the degree of cholesterol lowering is not surprising as participants with higher concentrations are more likely to have a greater reduction with treatment but will also have worse pre-existing vascular disease. Ravnskov's report shows how trials often bear little relation to clinical practice. The mean initial cholesterol concentrations in the trials given in table I show that, based on current recommendations,' most patients studied would not have received treatment other than dietary advice. We hope that clinical practice will not be swayed by the erroneous conclusions of this report.

EDITOR,-U Ravnskov's conclusions are misleading.' Several of the trials unsupportive of cholesterol lowering were of treatment with oestrogens or thyroxine, agents with other actions that preclude their widespread use in preventing coronary heart disease and to study the effects of cholesterol lowering. We have recalculated the odds ratios after excluding trials of these agents. The pooled odds ratios for all deaths and for fatal and non-fatal coronary disease were 0-83, 0-65, and 0 75 respectively (all highly significant) with a total study group of 114932, clearly supporting cholesterol lowering. These figures contrast greatly with the odds ratios for the excluded trials of 1- 14, 1 12 (both significant at p

Frequency of citation and outcome of cholesterol lowering trials.

LETTERS Early parenteral penicillin in meningococcal disease EDITOR, -There cannot be many general practitioners who, if asked about their worst waki...
612KB Sizes 0 Downloads 0 Views