Recent eLetters
Displaying 1-10 letters out of 31 published
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Re:Conflicts of interest
Submit responseDisclosure of conflicts of interest in Japanese randomized controlled trials
Dear Editor,
Disclosure of potential conflicts of interest (COI) is essential in interpreting randomized controlled trials with less risk of bias. In 2008, the Japanese Ministry of Health, Labour and Welfare issued an ethical guideline for clinical research that endorsed disclosure of potential COI 1. To assess impact of the guideline, we investigated the proportion of Japanese randomized controlled trial articles which disclosed COI published during 2009-2010.
We used ICHUSHI Web 2, the largest database of medical literature in Japan run by the Japan Medical Abstracts Society, to identify articles with the following characteristics; post-marketing, double-blind, randomized controlled trial of prescription drugs; published by official journals of medical associations belonging to the Japanese Association of Medical Science; conducted in Japan and by public research institute (i.e., not by pharmaceutical company).
We identified 18 articles which met the above criteria. Funding source(s) was disclosed in 56% (10/18). Pre-registration was indicated in 17% (3/18). Study endpoint was clearly specified in 50%. Most trials (88%) reported results favoring trial drugs over comparator drugs or placebo.
The 18 articles were published in 14 journals. In submission requirements of these journals during 6-12 months prior to the publication, disclosure of potential COI was requested in 43% (6/14). It was requested in 55% (6/11) of journals written in English and 0% (0/3) in Japanese.
These findings suggest that Health Ministry's guideline has not taken full effects, and that caution should be practiced in interpreting Japanese randomized controlled trials for their financial and scientific integrity.
References
1. Ministry of Health, Labour and Welfare. ethical guideline for clinical research,2008(http://www.mhlw.go.jp/general/seido/kousei/i-kenkyu/#4)
2. Japan Medical Abstracts SocietyVer.4(http://www.jamas.or.jp/)
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Perplexity.
Submit responseDear Editor,
As a practicing clinician, who reads Evidence Based Medicine to keep up to date with significant progress in medicine, I cannot help feeling perplexed about the review of Ambrosy and Gheorghiade on the article by Zannad et al (Eplerenone in patients withsystolic heart failure and mild symptoms, NEJM 2011; 364 : 11-21). Throughout their commentary, the reviewers fail to mention that the main conclusion of the study,namely that a potassium sparing diuretic is beneficial in systolic heart failure while increasing the risk of hyperkalaemia, is hardly innovative, since aldosterone-receptor blockade has been part of recommended therapy for a number of years (1,2). This being the case, it is also perplexing why Ambrosy and Gheorghiade fail to mention that the choice of a placebo in the control group, and the excess mortality hence recorded,is particularly difficult to justify under the Helsinki Declaration of Human Rights, according to which a new method should be tested against the best available alternative. Ethical considerations aside, such an unbalanced comparison artificially expands any measure of relative risk reduction in mortality achieved by Eplerenone. It also deprives the prescriber, perphaps not unintentionally in an industry-funded trial, of an answer to the question of whether the significant extra cost of this drug buys any substantial benefit over that achieved by Spironolactone. If the journal really prides itself in providing a fair and comprehensive review of recent medical developments, these omissions should be urgently rectified.
References
1) Hunt SA, Abraham WT, Chin MH et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the diagnosis and management of heart failure in adults : A report from the American College of cardiology Foundation/American Heart Association Task Force on Practice Guidelines; developed in collaboration with the International Sociaty for Heart and Lung Transplantation. Circulation 2010;121 (12):e258.
2) Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008 - The Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of teh European Society of Cardiology; developed in collaboration with the Heart Failure Association ot the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Failure 2008;10:933-989.
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Comment on "A qualitative approach to Bayes' theorem" by Medow and Lucey
Submit responseDear editor,
We welcome the publication of Medow and Lucey in the December issue, describing a qualitative approach to Bayes' theorem [1]. Especially because the authors provide a new impulse to the development of clinician-friendly strategies for teaching clinical decision making skills.
However, the approach proposed by the authors is not new. We reported a didactic model based on a visual representation of Bayesian logic on a logarithmic scale eight years ago in peer-reviewed journals [ 2-4]. Our logical frame is also categorical and similar to the one proposed here, but it is more elaborate: it allows for the extremes of the probability scale, it provides more test power categories, and it covers asymmetry of test results.
The authors report a major limitation of their model: it applies to the intermediate range of probabilities (10-90), leaving the very high post test probabilities often at stake in specialist care and the very low concerned in general practice to the discretion of the clinician. In our model, using a log odds scale, findings with a "weak" power allow to advance or regress half step towards or away from diagnosis, "good" arguments one step, "strong" arguments one and a half and "very strong" two steps. In the author's model only two categories of test values are considered, good and very good. In case of weaker tests, the authors propose to change the probability category scale. Our model offers four categories of power of tests, reportedly also used by Alan Turing 50 years ago, corresponding to the log10 of the likelihood ratio rounded to half the unit [5].
Finally, their model somehow suggests symmetry of test results, a major misconception of junior clinicians. This symmetry applies to their example of a nuclear stress test, but not e.g., to D-dimers which are useful to exclude a pulmonary embolism, but add almost nothing for confirmation of the diagnosis.
We apply this approach for more than a decade in under and post graduate teaching and in clinical decision making workshops in different countries of Europe, Asia, Africa and South America with enthusiastic acceptance by trainees, but the effect of training with this approach still needs thorough assessment [6].
References
[1] Medow MA, Lucey CR. A qualitative approach to Bayes' theorem. Evid Based Med 2011;16(6):163-167.
[2] Van Puymbroeck H, Remmen R, Denekens J, et al. Teaching problem solving and decision making in undergraduate medical education: an instructional strategy. Med Teach 2003;25(5):547-550.
[3] Van Den Ende J, Bisoffi Z, Van Puymbroek H, et al. Bridging the gap between clinical practice and diagnostic clinical epidemiology: pilot experiences with a didactic model based on a logarithmic scale. J Eval Clin Pract 2007;13(3):374-380.
[4] Van Den Ende J, Moreira J, Basinga P, et al. The trouble with likelihood ratios. Lancet 2005;366(9485):548.
[5] Good I. AM Turing's statistical work in world war II. (Studies in the history of probability and statistics XXXVII). Biometrika 1979;66(2):393-396.
[6] Moreira J, Bisoffi Z, Narvaez A, et al. Bayesian clinical reasoning: does intuitive estimation of likelihood ratios on an ordinal scale outperform estimation of sensitivities and specificities? J Eval Clin Pract 2008;14(5):934-940.
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Gate control pain modulation theory invalidates the control groups used in these RCTs
Submit responseDear Editors,
The dorsal horns are not merely passive transmission stations but sites at which dynamic activities (inhibition, excitation and modulation) occur. [18]
Via a series of filters and amplifiers, the nociceptive message is integrated and analysed in the cerebral cortex, with interconnections with various areas. [1]
The processing of pain takes place in an integrated matrix throughout the neuroaxis and occurs on at least three levels, at peripheral, spinal, and supraspinal sites. [9]
Knowledge of the modalities of pain control is essential to correctly adapt treatment strategies (drugs, neurostimulation, psycho-behavioural therapy, etc.).
Dysfunction of pain control systems causes neuropathic pain. [1]
Spinal Cord Stimulation modalities evolved from the gate-control theory postulating a spinal modulation of noxious inflow. [16] [2] [7] [11] [12] [15] [17] [20] [22] [23] [24] [25] [26]
It has been demonstrated in multiple studies that dorsal horn neuronal activity caused by peripheral noxious stimuli could be inhibited by concomitant stimulation of the dorsal columns. [8]
Pain relief was more prominent at pain ascending through C fibers than pain ascending through Adelta fibers [21]
Many theories on the mechanism of action of Spinal Cord Stimulation have been suggested, including activation of gate control mechanisms, conductance blockade of the spinothalamic tracts, activation of supraspinal mechanisms, blockade of supraspinal sympathetic mechanisms, and activation or release of putative neuromodulators. [14]
At present, Spinal Cord Stimulation is a well established form of treatment for failed back surgery syndrome, complex regional pain syndromes (CRPS), low back pain with radiculopathy and refractory pain due to ischemia. [4] [3] [8] [13]
Stimulation produced analgesia can provide a level of analgesia and efficacy that is unattainable by other treatment modalities. [19]
Spinal Cord Stimulation for the treatment of chronic pain is cost- effective when used in the context of a pain treatment continuum. [14]
Precise subcutaneous field stimulation is targeted to specific areas of neuropathic pain. [6]
We aim at attenuation or blockade of pain through intervention at the periphery, by activation of inhibitory processes that gate pain at the spinal cord and brain. [9]
Segmental noxious stimulation produces a stronger analgesic effect than segmental innocuous stimulation. [10]
That is exactly what intradermal sterile water or subcutaneous saline injections do!
Chloride, used in subcutaneous "sham" injections, independently regulates the pain pathway. [5]
In these studies there was no valid control group receiving sham injections.
In the past, other researchers, in similar studies, have also had difficulties in blinding and comparing with control groups. [4]
These RCTs simply compared an established therapeutic intervention to another established therapeutic intervention.
References
[1] Labat JJ, Robert R, Delavierre D, et al. Anatomy and physiology of chronic pelvic and perineal pain. Prog Urol 2010;20(12):843-52. Epub 2010 Oct 20.
[2] Moharic M, Burger H. Effect of transcutaneous electrical nerve stimulation on sensation thresholds in patients with painful diabetic neuropathy: an observational study. Int J Rehabil Res 2010;33(3):211-7.
[3] Shrivastav M, Musley S. Spinal cord stimulation for complex regional pain syndrome. Conf Proc IEEE Eng Med Biol Soc 2009;2009:2033-6.
[4] Kunnumpurath S, Srinivasagopalan R, Vadivelu N. Spinal cord stimulation: principles of past, present and future practice: a review. J Clin Monit Comput 2009;23(5):333-9.
[5] Price TJ, Cervero F, Gold MS, et al. Chloride regulation in the pain pathway. Brain Res Rev 2009;60(1):149-70. Epub 2008 Dec 31.
[6] Henderson JM. Peripheral nerve stimulation for chronic pain. Curr Pain Headache Rep 2008;12(1):28-31.
[7] Handwerker HO. From Descartes to fMRI. Pain theories and pain concepts. Schmerz 2007;21(4):307-10, 312-7.
[8] Stojanovic MP, Abdi S. Spinal cord stimulation. Pain Physician 2002;5(2):156-66.
[9] DeLeo JA. Basic science of pain. J Bone Joint Surg Am 2006;88 Suppl 2:58-62.
[10] Defrin R, Ariel E, Peretz C. Segmental noxious versus innocuous electrical stimulation for chronic pain relief and the effect of fading sensation during treatment. Pain 2005;115(1-2):152-60.
[11] Craig AD. Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 2003;26:1-30. Epub 2003 Mar 6.
[12] Staal JB, Hlobil H, van Tulder MW, et al. Return-to-work interventions for low back pain: a descriptive review of contents and concepts of working mechanisms. Sports Med 2002;32(4):251-67.
[13] Stojanovic MP. Stimulation methods for neuropathic pain control. Curr Pain Headache Rep 2001;5(2):130-7.
[14] Krames E. Spinal Cord Stimulation: Indications, Mechanism of Action, and Efficacy. Curr Rev Pain 1999;3(6):419-426.
[15] Costentin J. Pain and its main transmitters. Ann Pharm Fr 2000;58(2):77-83.
[16] Meyerson BA, Linderoth B. Mechanisms of spinal cord stimulation in neuropathic pain. Neurol Res 2000;22(3):285-92.
[17] Yaksh TL. Regulation of spinal nociceptive processing: where we went when we wandered onto the path marked by the gate. Pain 1999;Suppl 6:S149-52.
[18] Melzack R. From the gate to the neuromatrix. Pain 1999;Suppl 6:S121-6.
[19] Stanton-Hicks M, Salamon J. Stimulation of the central and peripheral nervous system for the control of pain. J Clin Neurophysiol. 1997;14(1):46-62.
[20] Humphries SA, Johnson MH, Long NR. An investigation of the gate control theory of pain using the experimental pain stimulus of potassium iontophoresis. Percept Psychophys 1996 ;58(5):693-703.
[21] Kakigi R, Watanabe S. Pain relief by various kinds of interference stimulation applied to the peripheral skin in humans: pain-related brain potentials following CO2 laser stimulation. J Peripher Nerv Syst. 1996;1(3):189-98.
[22] Davis P. Pain: opening up the gate control theory. Nurs Stand. 1993;7(45):25-7.
[23] Cambier J. Gate control of the nociceptive message: applications to the treatment of pain. Bull Acad Natl Med 1989;173(7):855-60; discussion 860-1.
[24] Benabid AL, Henriksen SJ, McGinty JF, et al. Thalamic nucleus ventro-postero-lateralis inhibits nucleus parafascicularis response to noxious stimuli through a non-opioid pathway. Brain Res 1983;280(2):217-31.
[25] Malow RM, Dougher MJ. A signal detection analysis of the effects of transcutaneous stimulation on pain. Psychosom Med. 1979 Mar;41(2):101-8.
[26] Goldman DE. Gate control of ion flux in axons. J Gen Physiol 1965;48:SUPPL:75-7.
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Accurate, but is it patient-centred?
Submit responseAlthough the accuracy of a mercury sphygmomanometer can be debated, automatic and semi-automatic devices which inflate the cuff often do so to well above the systolic pressure and can cause patients considerable discomfort even when an appropriate cuff size has been used. These devices frequently re-inflate for a variety of reasons, but out of control of the operator who is waiting for a reading.
Anecdotally, I have had several patients request I use what they call the "old fashioned" mercury sphygmomanometer at future consultations.
Conflict of Interest:
None declared
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Do not discard your mercury sphygmomanometers, yet.
Submit responseIt would not be surprising to find that the "error" rate in blood pressure determinations with the "old fashioned" sphygmomanometer was due, in part, to a faulty technique by the individuals taking the blood pressures. Remarkably, little or no time is spent in teaching medical students the proper technique for blood pressure determination including the appropriate cuff size to use, the various audible phases, etc. One cannot determine if there is an exaggerated second phase of Karotkoff sounds, which is an indicator of the presence of atherosclerotic disease, with an electronic blood pressure apparatus. Neither can one determine the presence of a pulsus paradoxicus with an electronic device. The relegation of the stethoscope to the rubbish bin or museum was predicted decades ago and has not yet taken place. I, for one, will continue to use my stethoscope and take my patients' blood pressures with a manual sphygmomanometer, thank you.
Conflict of Interest:
None declared
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Qualitative reasoning by elimination
Submit responseDear Editor,
Bayes theorem can only be applied properly when considering a single diagnosis or its absence e.g. the presence or absence of asymptomatic diabetes mellitus, hypothyroidism, hyperlipidaemia, cervical cancer, breast cancer, etc. These asymptomatic situations are very important in the clinical setting and also in the community. It is in these situations that the reasoning described in this paper can be used. However, much of our time is taken up with differential diagnosis, which cannot be modeled by Bayes theorem (which explains why it is not often used as pointed out by the authors).
When dealing with differential diagnoses, we must first choose a good diagnostic lead [1, 2, 3] (or pivot [4]) e.g. acute abdominal pain, which has a limited differential diagnosis. Tim de Dombal and his colleagues did something similar [5]. We then choose a diagnosis from the list (e.g. appendicitis) and look for findings (e.g. guarding) that occur commonly in that chosen diagnosis and rarely (or never) in at least one other diagnosis in the list (e.g. non-specific abdominal pain). This 'other' diagnosis thus becomes less probable (or is ruled out if the finding cannot by definition occur in people with that diagnosis). The chosen diagnosis (e.g. appendicitis) correspondingly becomes more probable. A 'definitive' or 'sufficient' criterion (e.g. a red swollen appendix at surgery would confirm a diagnosis.
A different 'reasoning by elimination theorem' is thus required to model this reasoning process, which uses Bayes theorem as the starting point of its proof [1, 2]. The author's qualitative approach in this paper could also be applied to this 'reasoning by elimination theorem' that models differential diagnostic reasoning.
References
1. Llewelyn DEH. Mathematical analysis of the diagnostic relevance of clinical findings. Clin Sci 1979;57(5):477-479.
2. Llewelyn H, Ang HA, Lewis K, et al. The Oxford Handbook of Clinical Diagnosis, 2nd ed. Oxford University Press, Oxford 2009;754- 772.
3. Lipschick GY, Von Feldt JM, Frame L, et al. The Oxford American Handbook of Clinical Diagnosis. Oxford University Press, New York 2009;18-27.
4. Eddy DM, Clanton CH. The art of diagnosis: solving the clinico- pathological conference. N Eng J Med. 1982;306:1263-1268.
5. Horrocks JC, de Dombal T. Computer-aided diagnosis: description of an adaptable system, and operational experience with 2,034 cases. Br Med J 1972; 2: 5-9.
Conflict of Interest:
None declared
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What is 'transparent' EBM?
Submit responseDear Editor,
Different individuals have adapted and adopted the principles of EBM to different degrees and in vastly different ways [1]. There is yet another approach to EBM, which goes back a long way in terms of verbal justification on ward rounds but which has not been put in writing and taught in that way until recently [2]. It involves specifying the 'evidence' obtained from the patient that was used for each diagnosis and decision.
Instead of simply listing diagnoses and actions after the history and examination, the 'patient's evidence' for each diagnosis can be placed in parentheses after each diagnosis (e.g. "Diagnosis 1: Acute bronchitis [Cough with yellow sputum for 5 days, sweats, no wheeze, no crackles on 20/11/11, all findings resolved by 25/11/11]". After each treatment or test, the diagnostic indication is placed in parentheses (e.g. "Amoxicillin 250mg tds for 5 days for diagnosis 1". The Oxford Handbook of Clinical Diagnosis [2] provides thousands of such examples for students and young doctors and suggests different formats for presenting the 'patient's evidence'.
Many 'problem oriented' computer systems allow these links to be made automatically for each episode of care. If the patient has many diagnoses then they can all be listed with their 'diagnostic evidence' and management [2]. These can be updated (ideally automatically by computer) after each clinical episode in hospital and general practice.
When 'transparent evidence-based summaries' of this kind were written on a cohort of 76 patients admitted to a hospital under my care, an audit showed that 45 (59.2%) of patients went home within 3 days compared with 161 out of 376 (42.8%) patients going home within 3 days when such summaries were not written on admission (a difference of 16.4%, P= 0.008). This appeared to happen because the nurses and doctors taking over care could understand what had been done quickly and easily and continue the care or change it if necessary without delay.
This approach of linking in writing individual patients' findings to diagnoses and management for patients and others to read can be termed 'transparent medicine'. When the patient's findings match those in evidence-based guidelines (or a supporting publication discovered during or after a ward round) then the process can be described as 'transparent EBM'. I doubt whether anyone would argue with this way of practising medicine, which combines written transparency with EBM.
If the public become widely aware of this approach, it might become ethically unjustifiable to practice 'non-transparent EBM' unless some RCT showed that non-transparent EBM was as safe, efficient and effective as 'transparent EBM'!
References
1. Glasziou P. Editorial: What is EBM? Evid. Based Med. 2011 16:129- 130; doi:10.1136/ebm-2011-100099
2. Llewelyn H, Ang HA, Lewis K, et al. The Oxford Handbook of Clinical Diagnosis, 2nd ed. Oxford University Press, Oxford 2009.
Conflict of Interest:
None declared
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Editor's reply to "Conflicts of Interest"
Submit responseI agree with Dr. Tomedi's assertion that one might question the credibility of a commentary written by someone who has received pharmaceutical industry support, or for a number of other reasons. It is for this reason that BMJ Group policies ask authors to acknowledge and openly state any competing interests (1), and as a result of this policy, Dr. Tomedi could become aware of them and consider them in reading the commentary. An alternative policy could be to prohibit any person who has received pharmaceutical company funding from writing a commentary. However, in some fields, many experts have received some such funding. In the specific case of this commentary (2), the commentator has raised a number of cautions about the results of the study he critically appraised. And the competing interests appear to span a number of sources (companies). It is certainly appropriate to question bias, and then use one's judgment based on the available information. I hope readers will continue to do this as they evaluate not only the methodology of articles in the medical literature, but also the context and other factors such as the qualifications of the authors, to the extent they can be evaluated.
References1. http://group.bmj.com/products/journals/instructions-for-authors/editorial- policies/
2. Thomas, Mike. Cross-over randomised controlled trial: Long- acting ?-agonist step-up therapy is more likely to provide best response, compared to inhaled corticosteroid or leukotriene-receptor antagonist step -up in children with uncontrolled asthma receiving inhaled corticosteroids. Evid Based Med 2010;15:167-168 Published Online First: 16 August 2010 doi:10.1136/ebm1117
Conflict of Interest:
None declared
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Conflicts of interest
Submit responseDear editor,
The important influence of pharmaceutical manufacturers on the medical literature, and the positive "spin" placed on results and conclusions, has been well documented. Given this pervasive problem, readers may question the credibility of the commentary of an EBM reviewer who has "received consulting fees from MSD, Schering, Novartis and GSK and received honoraria from Altana, Astra Zeneca, Boehringer Inglehiem, GSK, MSD, Merck Respiratory, Schering-Plough and Teva."
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