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Recent eLetters

Displaying 1-10 letters out of 41 published

  1. Author's response

    Dear Editor,

    I am very grateful to Ken Uchino for amplifying and clarifying the detail of some of the points I was trying to make within the word limits of a 'Perspectives' paper. I suggest there are four key elements:

    1. The epidemiology is indeed complex and I am neither an academic nor an epidemiologist. However, it would appear that we can agree that there is indeed a difference between 'younger old' (i.e. 65-75) and 'older old' (i.e. 80+), both in relative and absolute risk - albeit in opposite directions. The key point here is not the strength of the associations with age, but the magnitude of impact of treating the risk factor at any given age. This is where interventional trials come in.

    2. As I pointed out in my paper, the data about treating hypertension in 80+ year olds accumulated prior to HYVET were very suggestive of benefit; they predicted HYVET would give a definitive answer. HYVET - by far the largest trial looking at patients aged 80+ - failed to live up to this promise. Sadly, the premature termination of the trial (because of excess mortality in the placebo group) arguably raised more questions about the clinical applicability of its results, than the trial answered.

    3. The PROSPER trial examined the use of statins in European patients initially aged 70-82 (mean 75), and followed up for an average of 3.2 years. Nearly 20% of patients entered into the 4-week single-blind placebo lead-in period failed to proceed to the randomised period (either for using <75% or more than 120% of placebo, or because they refused to participate). This raises questions as to generalisability. Whilst reducing cardiovascular events, the intervention failed to show a reduction in stroke. I fully accept that absence of evidence is not necessarily evidence of absence, but this must surely raise questions as to the magnitude of any true effect.

    4. None of these trials looked into the patients' preferences and priorities re outcomes. I argue that these change significantly with advancing frailty and incapacity (which in turn increase disproportionately with, but are not confined to, increasing age).

    If we cannot even be certain of the ostensibly simple quantitative aspect of the decision (the certainty of the magnitude of the treatment effects), how can we properly weigh that up against the much more difficult to define qualitative aspects (the beliefs, values, and priorities of my patient)?

    My central point is that without robust evidence applicable to the patient in front of me - usually over 80, and often very frail - how can I help the patient to reach truly informed consent? I may well have some of the estimates of magnitude wrong, but the principle still stands. A treatment decision is only as strong as its weakest link. I suggest that there are so many weak links in this particular evidence chain that it is almost impossible to reach a decision that all doctors would support. Suggesting that a simple 'one size fits all' (i.e. algorithmic guideline- based) solution would be appropriate is simplistic. Without more data we cannot be sure.

    For all these reasons I strongly urge that we undertake randomised trials of withdrawals of treatment in real life elderly patients (both frail and robust). This has the potential to find out how much impact these interventions have in clinical practice, as opposed to in the rarefied environment of scientific clinical trials.

    In the UK NHS we arguably should have a real opportunity to use 'big data' in real life in this way to find out if there are any signals there amongst the noise. A simple pragmatic trial involving tens of thousands of people would surely have a good chance of giving us the information we need? If the NHS funded this with the money currently earmarked for hitting treatment targets in those over 80, it would not take long to answer this question.

    Conflict of Interest:

    None declared

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  2. Overreacting to possible over-treatment? Hypertension treatment in the very elderly.

    Dear Editor,

    While I agree with Dr Byatt that it is important to discuss with patients the choices of treating risk factors to prevent disease, the basis for the discussion needs to be clarified and fine-tuned.

    Epidemiology: The attributable risk of hypertension in stroke decreases in the elderly. This phenomenon may be partly because other factors such as atrial fibrillation become more dominant factor. Framingham Study quoted in the paper is only one study. Pooling data from multiple studies, Prospective Studies Collaboration has reported that that higher risk of stroke mortality is observed with higher systolic and diastolic blood pressures across blood pressure ranges into age 80s.[1] The relative risk conferred with higher blood pressure diminish with age, but still in age 80s, 20 mm Hg increase in systolic blood pressure (SBP) is associated with ~1.5 fold increase in stroke. That compares with ~2.8 fold increase in risk of stroke in age 40s. But the absolute risk difference with increase in SBP or DBP is greater in old age.

    Even if Dr Byatt's reading of epidemiologic data is correct, a lack of observed association disease (stroke) with a risk factor (hypertension) does not necessarily translate that intervening on the factor would not reduce disease. This was clearly shown in case of cholesterol, where no consistent association with stroke risk has been shown in multiple studies.[2] Yet, clinical trials using statin class of cholesterol lowering medications have shown that stroke is indeed reduced if the study size is large enough in both primary and secondary prevention settings.[3, 4] We cannot assume that because the contribution of hypertension is smaller as one gets older, that treatment would not reduce stroke.

    Trial data: There is a consistent finding from clinical trials of blood pressure reduction comparing different targets or regimens that SBP reduction of 10-20 mm Hg confer a relative reduction stroke by about 30- 40%. Most studies confirm that stroke is very sensitive to blood pressure.[5] The finding of the HYVET study mentioned consistent in relative risk reduction of fatal and nonfatal stroke by 30% (p=0.06) with SBP difference in 15 mm Hg between the groups. The study may have be underpowered to reach statistical significance.

    One needs to keep in mind that the risk of stroke is low in the relatively healthy elderly individuals in clinical trials that mostly consists of persons free of cardiovascular disease. HYVET study with 80 years of age or older and found a rate of stroke of 1.7% per year in the placebo group. Active treatment results in a number needed to treat of 94 over 2 years to prevent one stroke. For comparison, in ALLHAT, with the mean age of 67, the annual stroke rate was ~1% per year.[6]

    Primary prevention is a challenge because the event rate and absolute risk reduction by intervention is low, even if relative risk reduction is large. In the elderly, the risk of events is higher, but the time horizon is also shorter. The discussion should not necessarily focus on the absolute risk reduction and the number needed to treat, but put the context of the outlook of the elderly individuals into the next several years, some of whom are living into elderly age in relative good health. Prioritizing may be important. What are the important diseases to prevent, screen, treat? While Dr Byatt focuses on stroke, treatment of hypertension reduces strokes, congestive heart failure, and myocardial infarction. While I agree with the recent JNC 8 recommendation to question the same blood pressure target across ages, hypertension cannot be simply viewed as over treated.[7]

    References

    1) Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360(9349):1903-13.

    2) Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370(9602):1829-39.

    3) Taylor FC1, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. JAMA 2013;310(22):2451-2.

    4) Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8(5):453-63.

    5) Staessen JA1, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001;358(9290):1305-15.

    6) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997

    7) James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311(5):507-20.

    Conflict of Interest:

    None declared

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  3. Comment on "Need for standardising adverse event reporting in testosterone trials" by Basaria

    Dear Editor,

    We are very grateful for the positive comments from Dr Basaria about our meta-analysis of randomized controlled trials (RCTs) showing that testosterone therapy among men increases the risk of a cardiovascular -related event (1;2). As per the Preferred Reporting Items for Systematic Reviews and meta-Analysis (PRISMA) guidelines (item 25) (3), we also highlighted the limitations of our review. We are surprised that a comment on compliance with the PRISMA guidelines is followed by the sentence "Therefore, firm conclusions regarding the association between testosterone therapy and CVD cannot be drawn from this study" (1). This line of reasoning would preclude firm conclusions being drawn from all well-conducted meta-analyses of RCTs, which inevitably each have limitations as well as strengths. In a recent update of the Competing Interests statement associated with his commentary, Dr Basaria, and the editor, have clarified a number of potential conflicts of interest including connections with pharmaceutical companies selling or developing testosterone therapy, which may affect readers' interpretation of the commentary. A separate report describes the way pharmaceutical companies have subtly promoted testosterone therapy (4) despite growing evidence of its harmful effects.

    References

    (1) Basaria S. Need for standardising adverse event reporting in testosterone trials. Evid Based Med 2013.

    (2) Xu L, Freeman G, Cowling BJ, et al. Testosterone and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013;11(1):108.

    (3) Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097.

    (4) Braun SR. Promoting "Low T": A Medical Writer's Perspective. JAMA Intern Med 2013;173(15):1458-1460.

    Conflict of Interest:

    None declared

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  4. Potential aetiological significance of statin's raising glucose

    Dear Editor,

    Montori and Brito draw attention to the limited clinical significance of statins' raising glucose (1), consistent with the non-linear association of fasting glucose with cardiovascular disease (2). It is quite possible that the limited clinical significance of statins' minor effects on glucose also translates into limited aetiological significance. On the other hand, statins are not alone in having divergent effects on diabetes and cardiovascular disease. At least one other well-established therapy for preventing cardiovascular disease also has the same set of effects. Diuretics similarly both decrease the risk of cardiovascular disease but also increase the risk of diabetes. Conversely, some effective treatments for diabetes have been found to increase the risk of cardiovascular disease, such as rosiglitazone and sulphonureas. Notwithstanding, the very well-established relation between diabetes and cardiovascular disease, this consistent pattern from experimental evidence suggests the existence of an underlying exposure which may both protect against cardiovascular disease and cause diabetes.

    In randomized controlled trials testosterone therapy improves glucose metabolism (3) but increases the risk of cardiovascular-related events (4). Moreover, evidence from randomized controlled trials shows that statins reduce testosterone (5). Taking all this experimental evidence together raises the possibility that the mechanism underlying the divergent effects of statins on both diabetes and cardiovascular disease could be androgen modulation. Whether such a mechanism could also be relevant to the other therapies which also have divergent effects on diabetes and cardiovascular disease has never been considered. Notably spironolactone, which is known to decrease androgens, also has divergent effects on cardiovascular disease and diabetes, preventing mortality in heart failure but adversely affecting glucose metabolism (6). A small mechanistic randomized controlled trial examining whether the effects of statins on key factors in the ischemic pathway, such as markers of endothelial function or clotting factors (7), could be mediated by androgens, would provide confirmation or refutation. Androgen modulation as a contributor to the mechanism of statins, and perhaps other therapies, not only potentially provides a unified explanation for paradoxical results from randomized controlled trials, but also is consistent with the higher age-standardized rates of cardiovascular disease among men than women.

    References

    (1) Montori VM, Brito JP. Statins induce hyperglycaemia of uncertain importance. Evid Based Med 2013;18(4):157-158.

    (2) Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di AE et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375(9733):2215-2222.

    (3) Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011;34(4):828-837.

    (4) Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013;11:108.

    (5) Schooling CM, Au Yeung SL, Freeman G, Cowling B.J. The effect of statins on testosterone in men and women: a systematic review and meta- analysis of randomized controlled trials. BMC Medicine 2013;11:57.

    (6) Swaminathan K, Davies J, George J, Rajendra NS, Morris AD, Struthers AD. Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles. Diabetologia 2008;51(5):762-768.

    (7) Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation 2013; 127(2):251-257.

    Conflict of Interest:

    None declared

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  5. Reply to DeFrank and Brewer

    Dear Editor,

    We would like to thank DeFrank and Brewer for their interest in our recently published paper: Long-Term Psychosocial Consequences of False- Positive Screening Mammography.(1)

    In the Methods section DeFrank and Brewer write: "Brodersen and colleagues conducted a study of 454 adult women in Denmark screened in the same time period who had normal mammography screening results, false- positives or breast cancer diagnoses." We (Brodersen & Siersma) included 454 adult women in Denmark who had abnormal mammography screening results (false-positives or breast cancer diagnoses) and 864 women with normal screening results - all 1318 screened in the same time period.

    In the Methods section DeFrank and Brewer also state that the questionnaire we used: the Consequences Of Screening in Breast Cancer (COS -BC), is a revised version of the question: the Psychosocial Consequences Questionnaire (PCQ). This is not the case. Together with the developer of the original Australian version of the PCQ - deceased Professor Jill Cockburn - we published a systematic reviewed on "The adequacy of measurement of short and long-term consequences of false-positive screening mammography".(2) Part of our conclusion was: "The PCQ is an adequate questionnaire for measuring short-term consequences, and the PCQ is preferable to other measures because of its higher sensitivity. However, there is little evidence that the PCQ is able to adequately detect all long-term consequences of screening mammography. Given the inadequacy of the measurement instruments used, any current conclusions about the long-term consequences of false-positive results of screening mammography must remain tentative". In a qualitative study including six focus interviews with women having false-positive screening mammography we found that the PCQ includes ambiguous items, does not cover all psychosocial consequences of false- positive screening mammography and three items from the PCQ were deleted because they were judged by interviewees to be irrelevant.(3) We also found that the women's experiences in the critical period from abnormal screening mammography until final false-positive diagnosis differed entirely from their experiences after the final diagnosis.(3) Therefore, fifteen new items were generated to cover the negative psychosocial consequences of abnormal and false-positive screening mammography comprehensively.(3) Five new items were produced that concerned the consequences of screening mammography during the period after being declared ''free from'' suspicion of cancer.(3) Response options for the positive items were changed to allow responses in both positive and negative directions. Our conclusion was: "Because of the major changes to both parts of the PCQ the measure derived from this study should be regarded as a new questionnaire with two parts: Consequences Of Screening in Breast Cancer (COS-BC). Part II focuses on the long-term consequences of a false-positive screening mammography".(3) Because we had developed a new questionnaire (based on Jill Cockburn's work) we conducted two psychometric studies using the Item Response Theory Partial Credit Rasch model for polytomous items plus Classical Test Theory to validate the COS-BC.(4;5) Therefore, it is slightly confusing that DeFrank and Brewer calls COS-BC for PCQr when it actually is a new measure. Due to this extensive qualitative and statistical psychometrical work we have provided robust high quality evidence that the subscales of the COS- BC measure each distinct constructs that are unidimensional. It is therefore wrong when DeFrank and Brewer in the Commentary section write that some "subscales mix multiple constructs". Furthermore, we have revealed that the PCQ lacks content validity and encompass ambiguous items. Because the COS-BC has high content validity and adequate psychometric properties we can conclude that the COS-BC and the PCQ do not measure the same thing. It is therefore not appropriate that DeFrank and Brewer compare the scores of the PCQ with the scores of the COS-BC. Furthermore, standard methods, like the correlation coefficients are different from our linear regression methods, and do not adjust for the differential dropout. As stated in our method section: "We used generalized estimating equations methods to account for repeated measurement on the same individual. To adjust for possible bias resulting from differential dropout from the study, the scores available at each follow-up time point were weighted by the inverse of an estimate of the probability of this score being observed at that time point".(1) Those people that are worse off have the tendency to drop out in surveys. In our case, women diagnosed with breast cancer and the women that are most affected by the false-positive screening result could have a higher tendency to drop out; analysing only the subjects that did not drop out will then artificially decrease effects. By using inverse probability weighing and correcting the confidence intervals accordingly using generalized estimating equations we have adjusted for this differential drop out. The relatively small effect sizes found and commented on by DeFrank and Brewer using our data may well be an artefact of not adjusting for dropout.

    In the Commentary section DeFrank and Brewer also write that the COS -BC "has a subscale for breast self-examination, a behaviour that many guidelines now recommended against". However, the subscale has not anything to do with breast self-examination recommendations. In our qualitative study we found that women with false-positive screening mammography examined their breasts with their hands and examined their breasts in a mirror as a psychosocial consequence of the false-positive results and not because of any recommendation.

    In the Commentary section DeFrank and Brewer also write: "The second half of the PCQr assesses how patients...". Most of these women are not patients. The main part of the women in our survey had a normal or a false -positive screening result and besides that they were healthy. In the same sentence DeFrank and Brewer continue:"....think the testing affected them and uses an uncommon scoring system." We do not find the scoring system as a limitation since the response categories and scoring system for part 2 of the COS-BC were developed during the previous mentioned focus group interviews.(3) Furthermore, part2 of the COS-BC was validated using the empirical knowledge from these interviews,(3) the theory of cognitive dissonance, the theory of sense of coherence, and as mentioned above Item Response Theory Partial Credit Rasch model for polytomous items. (4;6)

    In the Commentary section DeFrank and Brewer lastly write: "Finally, the absence of analyses that demonstrate whether changes over time differed by test results, the internal consistency of measures and their reliability over time. Study findings would be strengthened by the inclusion of outcomes assessed before screening or learning of test results." Test for interaction between time and the three screening groups could have been added to the tables, but such test may not have been very informative because of the large differences between the trajectories in the start of follow-up: most tests for interaction were highly significant. Where items are shown to fit a Rasch model the measure can be shown to posses criterion-related construct validity,(7) to be objective (invariant),(8) sufficient(9) and, therefore, also reliable.(10) Furthermore, we have provided evidence that the items in the subscales do not posses differential item functioning in relation to time.

    References

    (1) Brodersen J, Siersma VD. Long-Term Psychosocial Consequences of False-Positive Screening Mammography. The Annals of Family Medicine 2013;11(2):106-15.

    (2) Brodersen J, Thorsen H, Cockburn J. The adequacy of measurement of short and long-term consequences of false-positive screening mammography. J Med Screen 2004 Mar 1;11(1):39-44.

    (3) Brodersen J, Thorsen H. Consequences Of Screening in Breast Cancer (COS-BC): development of a questionnaire. Scand J Prim Health Care 20081;26(4):251-6.

    (4) Brodersen J. Measuring psychosocial consequences of false- positive screening results - breast cancer as an example. Department of General Practice, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen: M?nedsskrift for Praktisk L?gegerning, Copenhagen. ISBN: 87-88638-36-7; 2006.

    (5) Brodersen J, Thorsen H, Kreiner S. Validation of a condition- specific measure for women having an abnormal screening mammography. Value in Health 2007;10(4):294-304.

    (6) Brodersen J, Thorsen H, Kreiner S. Consequences Of Screening in Lung Cancer: Development and Dimensionality of a Questionnaire. Value in Health 2010;13(5):601-12.

    (7) Rosenbaum PR. Criterion-related construct validity. Psychometrika 1989 ;54(4):625-33.

    (8) Rasch G. An Informal Report on a Theory of Objectivity in Comparisons. In: Van der Kamp LJTh, Vlek CAJ, editors. Psychological Measurement Theory.Leyden: University of Leyden; 1967:1-19.

    (9) Andersen EB. Sufficient Statistics and Latent Trait Models. Psychometrika 1977;42:69-81.

    (10) Bartholomew DJ. The Statistical Approach to Social measurement. San Diego: Academic Press; 1996.

    Conflict of Interest:

    None declared

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  6. Are Children at Unnecessary Risk of Medication Incidents?

    Dear Editor,

    Medication incidents are the commonest reported clinical incident in children and the second most common in neonates. [1] Current evidence is that the most effective method of reducing these incidents in the acute hospital is to have frequent attendance on the ward by a clinical pharmacist. [2,3] This was discussed by Chua in Evidence Based Medicine.[4]

    We wanted to see how many other units in Northern and Cumbria Regions of England were in a similar situation. A member of staff from each of eleven children's ward and neonatal units in the Northern Region of England was telephoned. (Great North Children's Hospital, Sunderland Royal Hospital, James Cook University Hospital, North Tyneside General Hospital, Carlisle Royal Infirmary, West Cumberland Hospital, South Tyneside General Hospital, Queen Elizabeth Hospital Gateshead, North Tees General Hospital and the two inpatient units in our Trust: University Hospital North Durham and Darlington Memorial Hospital). If they had a pharmacist visit three times a week or more to review inpatient and discharge drugs in real time they were scored as having ward based pharmacists. Weekly visits to provide a ward top-up service were not counted.

    Of the eleven neonatal units, five (45%) had clinical pharmacists. Of the eleven inpatient children's wards, five (45%) had clinical pharmacists. These five units were not the same for neonates and paediatrics.

    CDDFT is about to pilot a clinical pharmacist to support the paediatric and neonatal patients within the Trust. We wonder if this issue has been identified in other units and if so whether there are examples of innovative practice and outcome measures that address this?

    References

    1) National Patient Safety Agency. Review of patient safety for children and young people.

    2) Sanghera N, Chan P-Y, Khaki ZF et al. Interventions of Hospital Pharmacists in Improving Drug Therapy in Children. A systematic Literature Review. Drug Safety 2006 (11): 1031-1047

    3) McCartney RJ, McCartney RG, Postle JA et al. An Evaluation of Clinical Pharmacist Contributions in Paediatrics Arch Dis Child 2011 96:e1

    4) Chua SS. Errors detected in 19% of paediatric medication preparations and administrations across five hospitals in London. Evid Based Med 2010;15:123-124 doi:10.1136/ebm1087

    Conflict of Interest:

    None declared

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  7. Authors' Response: Postpartum bleeding is reduced with sublingual powdered misoprostol when compared with oxytocin injection, but a new formulation of misoprostol is unlikely to revolutionise postpartum haemorrhage care

    Dear Editor,

    We thank Beverly Winikoff and Jill Durocher for their thoughtful commentary.(1) Winikoff and Durocher note that the incidence of PPH in our study's (2) oxytocin group was higher than expected. This deviance can occur, particularly in studies with relatively small samples such as ours. Regardless, the randomization produced study groups with similar characteristics to each other,(2) although this particular sample of women had higher risk of postpartum hemorrhage than the general population, something that might be expected in the study hospital, a referral center.

    Our results were also consistent with a previously published study comparing sublingual administration of 400 mg tablet misoprostol with oxytocin, one among various criteria upon which causal associations are judged to exist that our study met.(3) We agree and question the pragmatism of a powdered formulation in the article.(2) The potential to reduce drug costs by 33% remains substantial for a medication that is widely recommended for PPH prevention.(4)

    We think there is little basis to question the drug potency in our study. The drug manufacturer, Astra-Zeneca provided us with the study medication directly, and we assume the potency was acceptable to the manufacturer upon distribution. Unlike the oxytocin stored under variable field conditions, potentially exposed to sunlight and high temperatures (potentially without refrigeration prior to their purchase in the cited Ghana study),(5) the packaged study medications were stored in a refrigerator maintained at 2 to 8 degrees Celsius within the clinical pharmacy department at our hospital until their use as stated in the manuscript.(2) What is not well known is whether intramuscular administration of oxytocin is less efficacious than oxytocin administered in intravenous solution; the Cochrane Review of uterotonics for PPH prevention typically analyzed IM and IV administration jointly(6) and whether the strong observed effect is attributable to the powdered formulation.

    We agree that further investigation of these issues will clarify the questions our article raises about sublingual administration of lower dose misoprostol for PPH prevention.

    References

    1. Winikoff B, Durocher J. Postpartum bleeding is reduced with sublingual powdered misoprostol when compared with oxytocin injection, but a new formulation of misoprostol is unlikely to revolutionise postpartum haemorrhage care. Evid Based Med. 2012 Nov 2. 10.1136/eb-2012-100966.

    2. Bellad M, Tara D, Ganachari M, et al. Prevention of postpartum haemorrhage with sublingual misoprostol or oxytocin: a double-blind randomised controlled trial. BJOG 2012;119:975-86.

    3. Rothman KJ. What is Causation?" in Epidemiology: An Introduction. Oxford University Press, New York. 2012;pp 33

    4. WHO recommendations for the prevention and treatment of postpartum haemorrhage 2012 http://apps.who.int/iris/bitstream/10665/75411/1/9789241548502_eng.pdf

    5. Stanton C, Koski A, Cofie P, et al. Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana. BMJ Open 2012;2:e000431.

    6. Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000494. DOI: 10.1002/14651858.CD000494.pub3.

    Conflict of Interest:

    None declared

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  8. It is unethical to give placebo

    Dear Editor, The trial has two arms: magsulf and placebo. In my opinion the subjects should give informed consent and instead of blinding the treatment, the subjects should be able to opt for which arm they would like to participate. And lastly, instead of placebo some other treatment like diazepam or phenytoin should have been given as denying treatment is unethical. Moreover, the magsulf has severe side effects e.g. respiratory rate goes down. Because of low therapeutic index, it has to be given cautiously.

    Conflict of Interest:

    None declared

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  9. How should we measure psychological consequences of false-positive screening mammograms adequately?

    Dear Editor,

    In this week's EBM, Bond and colleagues report a systematic review entitled: 'Psychological consequences of false-positive screening mammograms in the UK'.(1) Their two main outcomes are self-reported questionnaires, and attendance at the next screening round.

    Together with two colleagues, I conducted a systematic review in 2004 on the adequacy of measurement of short and long-term consequences of false-positive screening mammography.(2) We concluded that the generic measures (GHQ, HADS and STAI) "should not be used to measure psychological consequences of any kind of cancer screening" and that a condition- specific measure (PCQ) was preferable.(2) We also concluded, "Given the inadequacy of the measurement instruments used, any current conclusions about the long-term consequences of false-positive results of screening mammography must remain tentative."(2) Therefore, we conducted six focus group interviews to test the content validity of the PCQ in a time frame of 1-12 months after a false-positive screening mammography.3 Because we had to make major changes to the PCQ, we developed a new questionnaire: Consequences Of Screening in Breast Cancer (COS-BC).(3) We have validated the COS-BC using the Rasch Item Response Theory model and found that the measure is a reliable multi-dimensional instrument for short- and long- term psychosocial consequences of false-positive screening mammography.(4;5) Therefore, it is unfortunate that Bond and colleagues do not discuss the inadequacy of the psychological measures included in their systematic review, and that a valid and reliable self-reported outcome measure with high content validity does exist. The inadequacy of the generic measures included in Bond et al's review could also be a plausible explanation as to why they found that: "Heterogeneity was such that meta- analysis was not possible".

    It is also difficult to understand why Bond and colleagues have limited their review only to include trials conducted in the UK. Why should we expect different psychological reactions to a false-positive screening mammography in different countries? The COS-BC has been translated, adapted, and tested for relevance in a Swedish context, and we found essentially no differences in psychosocial consequences of false- positive screening mammography in Denmark and Sweden.(6) Together with other colleagues, I have conducted the same translation, adaptation, and test of relevance of the COS-BC in Norway, the Netherlands, and Germany, with the same result as in Sweden (these projects are in progress).

    The second outcome of Bond and colleagues is attendance to the next screening round after a false-positive mammography. In some countries, researchers have found that these women have a higher attendance to the next screening round than those with a normal screening result. In other countries, researchers have found the opposite, or similar attendance rates. In my qualitative single- and focus group-interviews, some women said that they did not dare to go to next screening after all they had experienced after a false-positive result.(4) Others said they did not dare to stay away.(4) If the psychological impact of a false-positive screening mammography can be ambivalent feelings about attendance to the next screening round, re-attendance is a poor surrogate outcome for the psychological impact of a false-positive screening mammography.

    References

    (1) Bond M, Pavey T, Welch K, et al. Psychological consequences of false-positive screening mammograms in the UK. Evid Based Med 2012.

    (2) Brodersen J, Thorsen H, Cockburn J. The adequacy of measurement of short and long-term consequences of false-positive screening mammography. J Med Screen 2004;11(1):39-44.

    (3) Brodersen J, Thorsen H. Consequences Of Screening in Breast Cancer (COS-BC): development of a questionnaire. Scand J Prim Health Care 2008; 26(4):251-256.

    (4) Brodersen J. Measuring psychosocial consequences of false- positive screening results - breast cancer as an example. Department of General Practice, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen: M?nedsskrift for Praktisk L?gegerning, Copenhagen. ISBN: 87-88638-36-7; 2006.

    (5) Brodersen J, Thorsen H, Kreiner S. Validation of a condition- specific measure for women having an abnormal screening mammography. Value in Health 2007;10(4):294-304.

    (6) Bolejko A, Wann-Hansson C, Zackrisson S, et al. Adaptation to Swedish and further development of the 'Consequences of Screening - Breast Cancer' questionnaire: a multimethod study. Scand J Caring Sci 2012.

    Conflict of Interest:

    None declared

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  10. Antiemetics and arrhythmias.

    Dear Editor,

    One third of patients who undergo surgery will experience postoperative nausea and vomiting (PONV) which can be very distressing (wound dehiscences and pulmonary complications)[1]. Rawlinson and colleagues [2] have made an excellent systematic review of randomised controlled trials, whose conclusions included the confirmation of intravenous dexamethasone and ondansetron (5-HT3 antagonist) as effective drugs for prophylaxis of PONV when compared to controls. However, a recent FDA safety alert [3]refers that a single 32 mg intravenous dose of ondansetron may affect the electrical activity of the heart (QT interval prolongation), which could predispose patients to develop an abnormal and potentially fatal heart rhythm known as "torsades de pointes". Additionally, ondansetron is a very expensive drug, which in the present financial crisis is very relevant. So, it may be useful to remember the old and low-priced antiemetic metoclopramide as a cheaper and safer alternative to ondansetron. Metoclopramide has not yet been associated with "torsades de pointes". As it blocks dopaminergic (D2) receptors, it is contraindicated in Parkinson's disease, and with chronic use may induce extrapyramidal reactions. But, for a single or short therapeutic course this problem seems not frightening, and furthermore, it has the advantage to increase GI motility, which may be useful to reduce the opioid gastric side effects, and if used before anaesthesia induction, it may also mitigate the danger of gastric content aspiration.

    Reference

    1- Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2441-51.

    2- Evid Based Med. 2012;17(3):75-80.

    3- FDA at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm272041.htm

    Conflict of Interest:

    None declared

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