Correspondence with the National Institute for Health and Clinical Excellence

This page lists correspondence with the National Institute for Health and Clinical Excellence. On 3 December 2012 BMJ editor in chief Dr Fiona Godlee wrote to NICE's chair, Professor Sir Michael Rawlins. In her letter she says: "Now that serious doubts have been raised about the evidence behind claims for oseltamivir’s effectiveness and safety, I am asking you to withdraw approval for oseltamivir until NICE has received and reviewed the full clinical trial data and those anonymised data are available for independent scrutiny."

 

All rapid responses

Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on bmj.com. Although a selection of rapid responses will be included as edited readers' letters in the weekly print issue of the BMJ, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window.

The prognosis of a terminally ill patient can never be determined with precise accuracy. For administrative purposes however the criterion that a doctor would be surprised if a patient remained alive after 6 months has worked well. At present, estimates of prognosis are used very widely when decisions that will shorten life are taken; for example, stopping ventilation or renal dialysis or withholding antibiotics. In general the evidence suggests that patients die earlier than their doctors think they will, so, if mistakes are made they are likely to be in the direction of over-estimating the length of time a patient has to go.

The legislation will ensure that the independent doctors carefully consider the possibility of coercion and take further advice from others who know the family if they are unsure. Great care will be taken to ensure that competence is thoroughly assessed.

Doctors who chose the medical profession solely to cure patients entered the wrong profession. A good doctor will care for patients at all stages of life and at all stages of illness, including terminal illness. The doctor will give primacy to an informed and competent patient’s wishes unless this is clearly inconsistent with the patient’s welfare.

Competing interests: Vice-Chair of Dignity in Dying, steering committee member of Healthcare Professionals for Assisted Dying (HPAD)
21 August 2014
Professor Philip Graham
Psychiatrist
London
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The evidence suggests that those who contemplate an assisted death are well aware of the wishes of their friends and relatives. They take these views into account before making a decision. Indeed sometimes they decide not to go ahead because of the distress it would cause their nearest and dearest. But if they choose to go ahead because of their own suffering that they regard as intolerable, they surely have the right to expect that those near to them will understand and accept that decision.

Depression is indeed sometimes difficult to diagnose in terminally ill patients, because of the overlap in symptoms. Dying people who are not depressed may lose appetite, sleep poorly and lack energy. But in most cases it is plainly obvious that the patient with a terminal illness contemplating an assisted death is competent to make the decision, understands its implications as well as the other options that are open. The relatively low figures of psychiatric referrals in Oregon reflect the fact that doctors screen out ineligible patients. In a small number of cases doctors call on the expertise of psychiatric professionals to help assess patients, the Falconer Bill would also strongly encourage this practice.

Yet the Falconer Bill differs from the law in Oregon as it states that ‘an assisting health professional must remain with the person until the person has –

a) self-administered the medicine and died; or
b) decided not to self-administer the medicine

Some patients will prefer to have a nurse whom they know well to be with them, while others will want their doctor to be present.

Competing interests: Vice-Chair of Dignity in Dying, steering committee member of Healthcare Professionals for Assisted Dying (HPAD)
21 August 2014
Professor Philip Graham
Psychiatrist
London
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The association between eating more fruit and vegetables and reduction in mortality, especially related to cancer and cardiovascular disease, is well established in this paper. One of the major challenges, however, is how we can translate this into practice.

With an increasing elderly population this poses difficulties for individuals who may no longer possess the physiological fitness required to source, prepare and consume fresh fruit and vegetables. More therefore needs to be done to help us understand how we can improve the diets of older people to prevent an increasing health burden which could be solved through simply eating more fruit and vegetables.

Competing interests: No competing interests
21 August 2014
James M Read
ST3 Geriatric Medicine / General Internal Medicine
Plymouth Hospitals NHS Trust
Derriford Hospital, Derriford Road, Plymouth, PL6 8DH
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Paul Nguyen makes the fair point that NNHs and NNTs derived from short term RCTs may be inaccurate. But for the purposes of personal decision-making we need only be ball-park estimates of costs, benefits, and harms. Many trials have long demonstrated that statins lower CVD events right across the risk range. The practical implication raises issues of Cost ( rationing ), Acceptability (personal choices), Safety ( mortality is NOT increased, but just how safe are statins ? ) , and Effectiveness ( 30% reductions in CVD event rates).

Way back in 1995 WOSCOPS (http://www.trialresultscenter.org/study2589-WOSCOPS.htm) provided the most relevant estimates for 45-64 year old men in the Glasgow region, demonstrating that (prava)statin reduced coronary events by 30%, and all-cause deaths by 22%, whereas the placebo group remained at an actual 7.5% five-year event-rate. Thus the Absolute risk reduction was 2.26% in 5 years, yielding an NNT of 220. Since then generic production of several statins has cut the price more than 20-fold.

Both Raj Bhopal and Richard Watson’s contribution testify to the vagaries of risk estimation ( Assign , QRisk and JBS3 all differing ).

They also both demonstrate the importance of ‘acceptability’. NICE has revised it’s position in the light of falling costs, and now advises that Statin prescription down to 10% ten-year Qrisk. Raj Bhopal decided not to take a statin, despite being above this threshold, whilst Richard Watson, despite being below the threshold, preferred to go for triple therapy. In my view both (as patients) are entitled to their decision, free from any personal abuse, using the best possible estimates of Cost, Acceptability, Safety, and Effectiveness in each CASE. Hence the need for robust debate in these columns, which may feel rough, but I do hope never abusive..

Competing interests: No competing interests
21 August 2014
L Sam Lewis
(re)tired GP
NHS
Surgery, Newport, Pembrokeshire, SA42 0TJ
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Can anyone tell me why the 'side effects' sections in the BNF do not list all the same symptoms as the drug information leaflets. Which is right which is wrong? If not in the BNF is it not deemed real? How do the BNF decide? Why did the author consider not consider using the BNF as one of its 'sources of information on adverse drug reactions?

Competing interests: No competing interests
21 August 2014
Michael Dunlop
GP
LE126UU
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Dear editor,

Poernan et al(1) have added a remarkable study to the ongoing debate over the safety of tranexamic acid (TXA) as a method of reducing perioperative blood loss. The scale of the data analysis is impressive. The effectiveness of TXA at reducing rates of transfusion post-operatively, particularly in hip and knee arthroplasty, is well established(2-4). It is encouraging that they find no increased incidence of adverse events amongst patients receiving TXA. Clearly efforts have been made to account for confounding variables but it is surprising that there is no mention of ischaemic heart disease as a variable.

This condition is common amongst patients undergoing arthroplasty and is a likely contributor to post-operative myocardial infarction, one of the study outcomes. If ischaemic heart disease was not accounted for results may be biased as these higher risk patients may be under represented in the TXA group. In turn this may contribute to the lower ICU admission rate amongst patients receiving TXA. In the accompanying editorial(5), Ker and Roberts rightly point out the need for a well constructed randomised controlled trial to conclusively demonstrate TXA safety, particularly in patients at high risk of thromboembolic events.

References
1. Poernan J, Rasul R, Suzuki S, Danninger T, Mazumdar M, Opperer Mboettner F, Memtsoudsis SG. Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. BMJ 2014; 349:g4829
2. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012 ;344:e3054
3. Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic acid in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br 2011; 93(12):1577-85.
4. Sukeik M, Alshryda S, Haddad FS, Mason JM. Systematic review and meta-analysis of the use of tranexamic acid in total hip replacement. J Bone Joint Surg Br 2011 ;93(1):39-46.
5. Ker K, Roberts I. Tranexamic acid for surgical bleeding. BMJ 2014;349:g4934.

Competing interests: No competing interests
21 August 2014
Andrew J Eggleton
Anaesthetics ST 5
Professor David Beverland
Royal Victoria Hospital, Belfast
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To the editor,

Although Dr Bao Wei et al. answered some of my questions (1), I still have concerns.

First, although the authors explained the reasons why three studies (2-4) we mentioned were excluded, it is still unclear why many studies on the relationship between fruit or vegetable intake and specific cancer mortality were finally excluded.

Second, as there was publication bias for their results, I still question whether the trim and fill method used by the authors can address the publication bias simply from a statistical perspective.

Zhihao

References
1. Authors' reply on the systematic review and does-response meta-analysis of fruit and vegetable consumption in relation to mortality.http://www.bmj.com/content/349/bmj.g4490/rr/762968
2. Mann JI, Appleby PN, Key TJ, Thorogood M. Dietary determinants of ischaemic heart disease in health conscious individuals. Heart. 1997;78:450-5.
3. Ness AR, Maynard M, Frankel S, Smith GD, Frobisher C, Leary SD, Emmett PM, Gunnell D. Diet in childhood and adult cardiovascular and all cause mortality: The boyd orr cohort. Heart. 2005;91:894-8.
4. Lo YT, Chang YH, Wahlqvist ML, Huang HB, Lee MS. Spending on vegetable and fruit consumption could reduce all-cause mortality among older adults. Nutr J. 2012;11:113.

Competing interests: No competing interests
21 August 2014
Zhihao Liu
Epidemiology
Jiangsu Centers for Disease Control and Prevention
No. 172 Jiangsu Road
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Patient empowerment is a useful way to increase compliance and monitoring in patients. It reduces the additional costs of frequent visits to doctors for regular follow up. For instance, in Diabetics and Hypertensives there is a serious need for monitoring of Blood sugar levels and BP recordings at specific intervals, on the basis of which effective treatment strategy can be planned by the practitioner. Not only does it reduce the burden on the doctor and help to engage the patients in useful informed conversation but it also builds a healthy patient-doctor relationship as well.

Competing interests: No competing interests
21 August 2014
Manjree Dube
Assistant Professor
Shanti Viswanathan
MGM Medical College
Navi Mumbai,India
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I have read the response from Dr Wei Bao et al. about the publication on fruit and vegetable intake and mortality. However, two questions were not addressed.

Firat, the authors emphasized the linear dose-response association in their orginal publication but simply described the non-linear assocaiton in both the Abstract and Results section. In my opinion, it was wrong and the results on the linear dose-response association should be deleted as there was evidence of curvilinear associations between fruit and vegetable combined or alone and all cause, cardiovascular, and cancer mortality (all P less than 0.05 for non-linearity). However, in their response, the authors still stick with the results on linear dose-response association.

Second, the marginal association (the upper limit of confidence interval for hazard ratios ranged from 0.98 to 0.99, approximately equal to 1. ) might be due to confounding factors or residual error. However, the authors did not mention this point in their response.

References
1. Authors' reply on the systematic review and does-response meta-analysis of fruit and vegetable consumption in relation to mortality.http://www.bmj.com/content/349/bmj.g4490/rr/762968

Competing interests: No competing interests
21 August 2014
Chibo Liu
Doctor
Department of Clinical Laboratory, Taizhou Municipal Hospital
381 Zhongshandong Road
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In the current heated debate over the benefits and harms of statins, many voices have requested the calculation and publication of the NNTs (number-needed-to-treat) and NNHs (number-needed-to-harm)1 in order to facilitate decision making with respect to individual patient treatment with statins in primary prevention.

However, the validity of extrapolating data from meta-analyses that incorporated trials of relatively short duration (median follow-ups from 1.8 year to 4.9 years), with the aim to calculate a 5-year (or 10-year) NNTs and NNHs may be questionable.

Truncated trials overestimate the reported benefits of any treatment. This overestimation is independent of prespecified rules and greater in truncated trials having fewer than 500 events.3 Therefore a 5-year (or a10-year) NNT based on extrapolation from data obtained by meta-analyses that included truncated trials with a relatively short duration, like ASCOT-LLA,4 or CARDS,5 JUPITER, 6 whose median follow-ups were 3.3 years, 3.6 years, and 1.8 years respectively, may overestimate the benefits and cannot be considered a reliable indicator for decision-making when considering starting a "lifelong" treatment for a specific patient.

Moreover the definitions of the so-called major adverse cardiovascular events (MACE), to which the calculated NNTs apply, should also be taken into consideration. These MACEs are most often composite end-points (made of “hard” end-points like deaths or cardiovascular deaths, mixed with “soft” end-points like diagnosis of unstable angina, non-fatal stroke, decisions for hospitalisations or for catheterisation and/or for stenting). The respective weight and the subjectivity to biases may differ for each individual MACE, especially for the “soft” end-points, which are quite prone to biases as they are not end-points per-se, but medical decisions, and therefore quite easily influenced by judgement or perception, particularly in non-blinded or poorly blinded trials.6

Much has been written about the proven and associated harms of statins, the evidence for which is accumulating. Meta-analyses do suggest that statins indeed increase the risk for new-onset diabetes.8 However, the 5-year (or 10-year) NNHs, if extrapolated from the data of these truncated trials, may still be underestimating the real harm for 3 main reasons. Firstly, randomised patients usually have been screened carefully and pre-exposed to the active drug through a run-in period thus excluding those intolerant to the study drug.9 Secondly, adverse events may be minimized10 or considered subjectively by the investigators as non-related to the study drug such as cases of rhabdomyolysis.11 Thirdly, the most serious adverse events may take variable time-periods to develop, such as occurrence of acute kidney injuries, as demonstrated by an elegant cohort study12 or a more recent observational study.13

Therefore, we caution that the 5-year (or 10-year) NNTs and NNHs calculated from meta-analysis that incorporated truncated trials may be inaccurate and misleading. There is a clear risk of underestimating the NNTs and overestimating the NNHs.

REFERENCES

1. Tresidder A. NICE should publish numbers needed to treat and harm for statins. BMJ 2014; 348: g3458.

2. Cholesterol Treatment Trialists (CTT) Collaborators. The effect of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet 2012: 380: 581-90.

3. Bassler D, Briel M, Mailovi VM, et al. STOP-IT-2 Study group. Stopping randomized trials early for benefits and estimation of treatments effects. Systemic reviews and metaregression analysis. JAMA 2010; 303 : 1180-7.

4. Sever PS, Dahlöf B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations in the Anglo-Scandinavian cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised trial. Lancet 2003; 361(9374): 1149-58

5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Collaborative atorvastatin diabetes study (CARDS). Lancet 2004; 364(9435): 685-96.

6. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195-207.

7. Nguyen PV. Electronic health records may threaten blinding in trials of statins. BMJ 2014; 349:g5239.

8. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010; 375:735-742.

9. Anonymous. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and antioxidant vitamin supplementation in a wide rage of patients at increase risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999; 20: 725-741.

10. Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin myopathy : A common dilemma not reflected in clinical trials. Clev Clin J Med 2011; 78: 393-403.

11. Ravnskov U, Rosch PJ, Sutler MC. Letter. N Eng J Med 2005, 353 (1): 94.

12. Hippisley-Cox H, Coupland C. Unintended effects of statins in men and women in England and Wales : population based cohort study using the QResearch database. BMJ 2010; 340: c2197.

13. Dormuth CR, Hemmelgam BR, Paterson JM, et al. Use of high potency statins and rates of admission for acute kidney injury : multicentre, observational study of administrative databases. BMJ 2013:346: f880.

Authors:

Paul v Nguyen MD, Internal Medicine Specialist, Centre Hospitalier Universitaire de Montréal, Montréal, Canada
Pierre Biron, MD, Pharmacology Professor (Retired), Université de Montréal, Montréal, Canada

Competing interests: No competing interests
21 August 2014
Paul v Nguyen
MD
Pierre Biron
Centre Hospitalier Universitaire de Montréal
Montréal, PQ, Canada H2W1T8
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