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Rapid Responses: Rapid Responses published:
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Limitations of Meta-analysis may cloud Primary Outcome Differences
- Ameet Bakhai, Kostas Zacharias (4 April 2006)
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Meta-analysis of lipid lowering treatment: abstract misleading?
- Mieke L van Driel, Pierre Chevalier, editor of Minerva Belgian Journal for evidence based medicine; Centre Universitaire de Médecien Générale, Université Catholique de Louvain, Belgium; (11 April 2006)
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Lipid Lowering Therapy in Diabetes – Ophthalmic Benefits
- Hiten G Sheth, Sher Aslam and Nigel Davies. (14 May 2006)
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Benefits more ? Relatives and Absolutes...
- L S Lewis (15 May 2006)
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Determining the threshold for statin treatment in people with type 2 diabetes
- Peter T. Donnan, Louise Donnelly, John New, and Andrew Morris (15 June 2006)
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Ameet Bakhai, Consultant Cardiologist Barnet & Chase Farm & Royal Free NHS Trusts, London, EN5 3DJ, Kostas Zacharias
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The meta-analysis publication by Costa et al. is helpful in highlighting the impact of lipid therapy for diabetic and non-diabetic patients however with due respect, some key clarifications are needed before we can fully appreciate the results. Firstly the meta-analysts should make an attempt at gaining individual patient level data from trials irrespective of how difficult this may be. Secondly it is not clear how many endpoints were collected in the publications of the trials - i.e. the trial publications mostly present statistics only on first or worst events for a patient - not all events. Given this key limitation it may somewhat inappropriate to report revascularisation events as part of the primary outcomes since these are inevitable down the line for patients and adding them to a mixture of hard events such as death and myocardial infarction may dilute clinically meaningful effects. For presumably space reasons the endpoints for the primary outcome are not reported individually and this again means readers may not have an accurate picture of the full benefits or lack of these. We appreciate the above limitations may be predictable in such papers but authors may be better stating these limitations as a priority and should concentrate efforts to avoid them with patient level data or avoid mixing apples and oranges. This does not detract from the considerable work undertaken by Costa et al. but raises a caution when appreciating these important results. Competing interests: None declared |
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Mieke L van Driel, MD, researcher, editor of Minerva Belgian Journal for evidence based medicine Dept. General Practice & PHC, Ghent University, De PIntelaan 185 UZ 1K3, B-9000 Ghent, Belgium, Pierre Chevalier, editor of Minerva Belgian Journal for evidence based medicine; Centre Universitaire de Médecien Générale, Université Catholique de Louvain, Belgium;
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The meta-analysis by Costa et al addresses clinically relevant issues by evaluating the effect of lipid lowering therapy in primary versus secondary prevention and diabetics versus non-diabetics.(1) The authors' conclusions as reported in the abstract may have important implications for guideline recommendations and marketing of statins. In our opinion the abstract does not provide the objective information needed for a correct interpretation of the results of this meta-analysis. The abstract reports relative risk reductions (RRR) as the measure of effect for the primary outcome. They seem impressive and are statistically significant. But when we read the article, we notice that the absolute risk differences, in particular those in primary prevention, are much less impressive and not all risk differences are statistically significant. The overall baseline risk in the non-diabetic population calculated from the event rate in the placebo group is 8%. The reduction that can be achieved through lipid lowering therapy in this group is 2%, reducing the risk of a coronary event to 6%. In the diabetic population the baseline risk is only slightly higher at 10%. The absolute risk reduction in this subgroup is also calculated as 2%. However, this difference is not statistically significant (-0.04 to 0.00; p=0.1). The authors fail to address this and focus only on their ‘positive’ findings expressed as RR’s and RRR’s. Although relative effect measures are a valid and widely accepted way to report outcome they cannot be interpreted without knowledge of the event rate without treatment.(2) The abstract of the meta-analysis does not provide this information. In addition, a measure of absolute effect (the risk difference), the “most natural statistic to use when considering clinical significance”(2), is not reported in the abstract. Therefore we argue that the abstract of this meta-analysis does not provide clinicians with sufficient information to guide their practice. Moreover, it seems to lack objectivity and the conclusion may even be misleading. The abstract is the most read part of a paper and its potential impact on clinical practice is high. It is often the first (and only) encounter with a trial through Medline. It goes without saying that the information in the abstract should be scientifically sound and objective.(3) We plea to the editors of the BMJ to protect its readers from over optimistic reporting that is not supported by the scientific data and to safeguard the objectivity of abstracts published in the journal. References: 1. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta- analysis of randomised controlled trials. BMJ 2006 doi:10.1136/bmj.38793.468449.AE (published 3 April 2006. 2. Deeks JJ, Altman DG. Effect measures for meta-analysis of trials with binary outcomes. In: Egger M, Davey Smith G, Altman DG, editors. Systematic reviews in health care. Meta-analysis in context. 2nd edition. London: BMJ Publishing Group, 2001:318-21. 3. Davidoff F, DeAngelis CD, Drazan JM, et al. Sponsorship, authorship, and accountability. Lancet 2001;358:854-6. Competing interests: None declared |
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Hiten G Sheth, specialist registrar Department of Ophthalmology, Chelsea & Westminster Hospital, 369 Fulham Rd, London SW10 9NH, Sher Aslam and Nigel Davies.
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Editor – we were read with interest your recent article on lipid lowering drugs in diabetes.(1) The authors and your readers may be unaware of the ophthalmic benefits of such therapy. Diabetic maculopathy is a common cause of loss of sight in such patients and is characterised by retinal oedema and lipid exudates. The use of atorvastatin in diabetic maculopathy has recently been shown in a randomised controlled trial to decrease visible lipid exudates and also have a positive effect on the visual outcome of affected patients.(2) This study also confirmed that exudates may reduce or resorb within weeks of commencing statin therapy and even prior to or without the need for argon laser photocoagulation, and this has been our experience also. The Wisconsin Epidemiologic Study of Diabetic Retinopathy(3) first identified an association between elevated serum cholesterol and hard exudates, this was confirmed in the Early Treatment Diabetic Retinopathy Study(4) and the FIELD study recently showed a 30% reduction in laser interventions required in type 2 diabetic patients receiving fenofibrate versus the placebo group.(5) We have recently followed a case series of patients with type 2 diabetes in ophthalmic outpatients and our series confirms the dramatic anatomical resolution of retinal hard exudates that may result from modifying the lipid profile in patients with type 2 diabetes, although this may not necessarily be associated with an improvement in Snellen visual acuity, as Snellen acuity is an extraordinarily crude test of visual function. In conclusion, statin therapy and lipid lowering in general not only confers primary and secondary cardiovascular protection, but is an emerging and exciting adjunctive therapy in gaining control in exudative diabetic maculopathy, where argon laser therapy has traditionally been the only treatment option. Hiten G Sheth specialist registrar Sher Aslam senior house officer Nigel Davies consultant Department of Ophthalmology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH 1. Costa J, Borges M, David C, Carneiro AV. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: metaanalysis of randomised controlled trials. BMJ 2006; 332:1115-8. 2. Gupta A, Gupta V, Thapar S, Bhansali A. Lipid-lowering drug atorvastatin as an adjunct in the management of diabetic macular oedema. Am J Ophthalmol. 2004 Apr;137(4):675-82. 3. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol 1989; 107: 244-49. 4. Chew EY, Klein ML, Ferris FL 3rd, Remaley NA, Murphy RP, Chantry K, Hoogwerf BJ, Miller D. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol. 1996 Sep;114(9):1079 -84. 5. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus: randomised controlled trial. Lancet 2005;366:1849-61. Competing interests: None declared |
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L S Lewis, GP Surgery, Newport, Pembrokeshire, SA42 0TJ
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Costa et al draw the principle conclusion that diabetic
patients benefit more, in both primary and secondary prevention. But it is abundantly clear from their own analysis that the
relative risk reduction was similar across ALL categories of patient. I quote :- the risk reduction for major coronary events was 21% (95%
confidence interval 11% to 30%; P < 0.0001) in diabetic patients and 23%
(12% to 33%; P = 0.0003) in non-diabetic patients. In secondary prevention, the
corresponding risk reductions were 21% (10% to 31%; P = 0.0005) and 23% (19% to
26%; P 0.00001). 'Blood lipids
were reduced to a similar degree in both groups.' ‘However, the absolute risk difference was three times
higher in secondary prevention. When results were adjusted for baseline risk,
diabetic patients benefited more in both primary and secondary prevention.’ Undaunted, they press on.. ‘when we adjusted the results
for baseline risk diabetic patients benefited more than non-diabetic
patients in secondary prevention for coronary artery disease death,
non-fatal myocardial infarction, revascularisation, and stroke. This
difference did not reach significance for primary prevention of
major coronary events.’ The NNTs remain as expected, reflecting, as they must,
the absolute baseline risk and the 22%
risk reduction across the board. Costa
adds nothing new in recognising that, all other things being equal, diabetics
have a higher absolute coronary risk. So what does this study add
? There are NO new important clinical
implications, for primary prevention in patients with type 2 diabetes. It confirms that we should not change
our guidelines. Patients will benefit from lipid-lowering in accordance with their absolute cardiovascular risk. We should continue to target treatment according to best available predictions of absolute cardiovascular risk. Progress will come from improving the 'targetting-of-those-at-greatest-risk', the accuracy of risk prediction, and finding cheaper, safer and more acceptable treatments. Competing interests: None declared |
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Peter T. Donnan, Senior Lecturer Mackenzie Building, Community Health Sciences, University of Dundee DD2 4BF, Louise Donnelly, John New, and Andrew Morris
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We were pleased that the BMJ published a meta-analysis of published trials of statins demonstrating that people with diabetes receive major benefit in terms of averting complications (1). Costa et al (1) conclude that there is a need to “define the threshold over which diabetic patients must be treated”, since it is still controversial whether statins should be prescribed in patients with low risk of coronary disease (2). Current guidelines are based on risk prediction from mainly Framingham-based algorithms, which underestimate coronary heart disease risk in people with type 2 diabetes (3). We have recently published a population-based algorithm which predicts risk of major coronary heart disease events in people with type 2 diabetes incorporating diabetes-specific factors such as glycaemic control (4). In a cash-limited health service such algorithms provide a useful decision aid since blanket prescribing has not yet been shown to be a cost-effective option. Peter T. Donnan, Senior Lecturer in Medical Statistics, University of Dundee Louise Donnelly, Research Fellow, University of Dundee John New, Consultant Diabetologist, Salford Andrew Morris, Professor of Diabetic Medicine, University of Dundee References 1.Costa J, Borges M, David C, Carneiro AV. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomized controlled trials. BMJ 2006; 332: 1115-8. 2.Garg A. Statins for all patients with type 2 diabetes: not so soon. Lancet 2004; 364: 641-2. 3. Brindle P, Beswick A, Fahey T, Ebrahim S. The accuracy and impact of risk assessment in the primary prevention of cardiovascular disease: a systematic review. Heart 2006; doi 10.1136/hrt.2006.087932 4. Donnan PT, Donnelly L, New J, Morris AM. Predicting the absolute risk of major coronary heart disease (CHD) events in type 2 diabetes in the United Kingdom population. Diabetes Care 2006; 29: 1231-36. Competing interests: The respondents are authors of a Diabetes Care article on the derivation and validation of an algorithm to predict major coronary heart disease events in people with type 2 diabetes funded by Diabetes UK and Pfizer UK. Dr New has received educational grants from Pfizer. |
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