This fascinating paper has a serious flaw; the exclusion of all studies with treatment-as-usual (TAU) comparison conditions. The authors justify this decision by stating that TAU is not standardized and cannot be considered an inactive condition. However, the difference between TAU and two included control conditions (wait-list and no care) may be predominantly semantic. Patients randomized to no care or wait-list cannot be forbidden from continuing to participate in the healthcare system and may receive exactly the treatments that they would usually receive if they were not enrolled in a clinical trial; that is, treatment as usual. No care and wait-list may not be any more standardized than TAU. Furthermore, TAU is what happens in the real world. Given the state of the mental health infrastructure in many countries, behavioural treatments are often compared against TAU to see if they are beneficial compared to what the patient would receive otherwise.
I have read the authors’ report on the investigation of data collection mode effects during administration of a three-item patient-reported patient-centered communication measure with interest. While I greatly appreciate the work the authors invested in the study, I think one of their major conclusions is not supported by the reported analyses. It is repeatedly stated throughout the manuscript that the relative clinician performance rankings were stable across the different data collection modes. However, the analytic strategy described in the Methods section, the perfectly identical distances between physicians (on the logit-scale) across modes in Figure 1, and the detailed results made available in the Supplementary Appendices suggest that they included the clinician identifiers as main effects in the analyses without specifying an interaction term between data collection mode and physician identifiers. This means that the ranking of (and even equal metric distance in logit units between) clinicians was restricted to be identical across all levels of the covariates, including administration mode, by the statistical model. In other words, the stable clinician ranking was rather a non-falsifiable assumption than a finding of the analyses.
This does not mean that the authors’ conclusion is necessarily wrong, only that the performed analyses did not check the hypothesis of constant clinician ranking across modes as intended. Additional analyses may show that this hypot...
I have read the authors’ report on the investigation of data collection mode effects during administration of a three-item patient-reported patient-centered communication measure with interest. While I greatly appreciate the work the authors invested in the study, I think one of their major conclusions is not supported by the reported analyses. It is repeatedly stated throughout the manuscript that the relative clinician performance rankings were stable across the different data collection modes. However, the analytic strategy described in the Methods section, the perfectly identical distances between physicians (on the logit-scale) across modes in Figure 1, and the detailed results made available in the Supplementary Appendices suggest that they included the clinician identifiers as main effects in the analyses without specifying an interaction term between data collection mode and physician identifiers. This means that the ranking of (and even equal metric distance in logit units between) clinicians was restricted to be identical across all levels of the covariates, including administration mode, by the statistical model. In other words, the stable clinician ranking was rather a non-falsifiable assumption than a finding of the analyses.
This does not mean that the authors’ conclusion is necessarily wrong, only that the performed analyses did not check the hypothesis of constant clinician ranking across modes as intended. Additional analyses may show that this hypothesis is supported by the data. For this, results based on a model that allows for interaction between data collection mode and clinician should be made available. If the estimated interaction parameters were shown to be both statistically and practically insignificant, and if the model with the interaction term did not show a substantially better fit to the data than the model without the interaction term, the authors’ conclusion would be supported. In a time of emerging data collection possibilities and the need for comparability of information on patient-centered communication from different sources, it would be great news.
Balen et al have responded to our papers. [1,2] In our BMJ open paper we systematically identified 276 claims of benefit relating to 41 different fertility interventions and 16 published references were cited 21 times on 13 of the 74 websites we searched.[1] In our BMJ analysis paper, we systematically examined the evidence for ‘38 additional fertility interventions’ and found evidence of improvements in live birth rates for only five interventions. We used standard critical appraisal techniques (as detailed in our paper) to explore the quality of these studies. We identified that for all five of these interventions the studies had methodological problems, raising uncertainty about the significance of the results. This is a serious issue for patients, public health, public trust, and regulators.
Balen et al suggest that our evidence review included - and found evidence lacking for - things which are not “add-ons”. We classified ‘add-ons’ in the BMJ analysis article in response to peer review where the issue was discussed (see online peer review comments).
Peer review comment: ‘The methodology has led them to five interventions for which there may be some evidence of improvement in live birth rates. One of these is intrauterine insemination in a natural cycle. This is an alternative treatment, rather than an “add-on”, and usually not one applied to the population who require IVF, and certainly not one intended to...
Balen et al have responded to our papers. [1,2] In our BMJ open paper we systematically identified 276 claims of benefit relating to 41 different fertility interventions and 16 published references were cited 21 times on 13 of the 74 websites we searched.[1] In our BMJ analysis paper, we systematically examined the evidence for ‘38 additional fertility interventions’ and found evidence of improvements in live birth rates for only five interventions. We used standard critical appraisal techniques (as detailed in our paper) to explore the quality of these studies. We identified that for all five of these interventions the studies had methodological problems, raising uncertainty about the significance of the results. This is a serious issue for patients, public health, public trust, and regulators.
Balen et al suggest that our evidence review included - and found evidence lacking for - things which are not “add-ons”. We classified ‘add-ons’ in the BMJ analysis article in response to peer review where the issue was discussed (see online peer review comments).
Peer review comment: ‘The methodology has led them to five interventions for which there may be some evidence of improvement in live birth rates. One of these is intrauterine insemination in a natural cycle. This is an alternative treatment, rather than an “add-on”, and usually not one applied to the population who require IVF, and certainly not one intended to increase live birth rate.’
Our response: ‘We have also added a further table 1: Classifications of IVF Interventions: This is the only reference in the HFEA we could find on the words ‘add-on’ which was only discussed at the Feb 2016 meeting: 'The committee discussed which techniques are more common or established and may be incorporated into other sections of the website. The committee agreed that the remaining techniques for discussion could be placed onto a page about ‘Treatment add-ons’. And we note there is no current definition of what is an ‘Add-on’ treatment as it very much depends on what [the] clinic offers.'
We, therefore, classified 27 of these as ‘Add-on’ interventions: six as alternative treatments to IVF and five treatments for the preservation of fertility (see Table 1 in the paper). We, therefore, followed the advice of peer review. By ‘we’ we mean two general practitioners adjudicated and all authors confirmed the classifcation. Of note, there were concerns that we are not fit to do this. However, the HFEA’s advice is that when it comes to IVF “you should talk to your GP to go through the options available”.
Also in response to peer review, we added to our conclusion the following: ‘Clinics vary significantly in what they offer and there is a lack of clarity on what actually constitutes an ‘Add-on’ intervention. Clear classification systems could aid understanding and reduce variation in what is offered to couples.’
I also draw your attention to the HFEA Press statement at the time that did not question our classification. HFEA statement on fertility treatment 'add-ons' 28 November 2016 (http://www.hfea.gov.uk/10541.html)
HFEA official response to BBC Panorama regarding fertility treatment 'add-ons'.
‘UK fertility clinics generally provide excellent patient care. However, an increasing number of patients tell us they feel unsure about IVF treatment add-ons – whether they work and are worth the extra cost. This puts pressure on patients to make difficult decisions at what is already a stressful time for them.
'We are concerned about the recent step change in the use of treatment add-ons. Unfortunately, we have limited powers to stop clinics offering them, nor to control pricing. Instead, we publish information directly for patients, so that they can have the facts at their fingertips before they go to a clinic and are able to make informed decisions and properly consent to treatment.
'With expert advice from our scientific committee, we have for some years been publishing information about add-ons such as reproductive immunology and PGS, making it clear whether or not they are proven to be effective. We are also working on producing information for our new website about a wider range of add-ons, introducing a simple labeling system to highlight their levels of effectiveness and potential harm.’
Balen et al, therefore, appear to disagree with our categorisation of the 27 interventions as add-ons (see Box 2 of the paper). [2] This is a matter for reasonable debate, but more importantly suggests a lack of outward clarity to many users of this information, notably patients. We stand by our methods (we searched systematically for a classification system at the outset), and to the best of our knowledge, The BMJ is the only journal to have a published classification system.
Regardless, of whether Balen et al prefer to categorise interventions as “add-ons” or part of core treatment, this does not affect our conclusion: there is little or no evidence supporting interventions available from UK fertility clinics to improve live birth rate. We note that this is not a conclusion that is directly challenged by Balen et al.
Balen et al criticise our research team on the grounds that we are evidence based medicine researchers, clinicians, and epidemiologists, not “specialists in reproductive medicine”. This would seemingly seem an unusual line of argument. Given the known concerns over potential conflicts of interests in the IVF industry, and the extensive list of conflicts highlighted at the end of Balen et al’s letter, it was paramount that this work was conducted by an independent group with no ties to the IVF industry. [3] That said, should the opportunity arise for further work assessing the quality of evidence for fertility interventions we would be happy to consider collaborating with co-signatories to improve the evidence-base.
Balen et al appear to object to our use of “live birth” as the core metric of success. Once again, this appears to be an unusual line of argument to take. We refer Balen et al to our recent paper in Trials Journal entitled “Why clinical trial outcomes fail to translate into benefits for patients”. [4] In this paper we highlight some of the issues with substantial amounts of clinical research utilising surrogate, composite and subjective endpoints and failing to take account of patients’ perspectives when designing research outcomes. We agree with Barnhart, who highlights the need for the reproductive industry to make live births as the correct, patient focused, outcome for trials evaluating therapies for infertility. [5] We were therefore pleased to see that live birth rates are being used as a key outcome by RCTs currently recruiting patients in the UK.
Balen et al say that the sector has been well regulated by the HFEA. We question the strength of their argument to support this. Following the publication of our paper, we were pleased to note that the HFEA themselves have committed to updating their evidence to ‘provide free, clear and impartial information to all affected by assisted reproduction,’ and to provide clear evidence-based information to patients and the public as stated in their 2017 innovation and regulation plan. [6] We also noted that the Director of Strategy at the HFEA, Juliet Tizzard, publicly stated, in reference to our work, that the HFEA “don't regulate this but do care deeply.” [7]
Balen et al also comment that we highlight the intervention “Intralipid”, which they suggest is not widely used. This suggestion is not in keeping with our systematic findings. Our analysis stemmed from identification of claims of benefit on fertility centre websites, and we found three such instances claiming benefits for Intralipid; however, Intralipid is offered more widely (four offer Intralipid without stating a claim benefit on the website), meaning approximately 1 in 10 of the clinics we searched offer this intervention. We highlighted our concern for the widespread advocacy of Intralipid, especially given the lack of evidence for this intervention, as noted by both the BFS and Royal College of Obstetricians and Gynaecologists. [2]
Balen et al state that ‘many of the items have a clearly defined role in specific situations; e.g. for a man with a physical blockage sperm has to be extracted surgically, frozen and used in an IVF cycle combined with intra-cytoplasmic sperm injection (ICSI).’ We agree and ICSI was not categorised as an ‘add-on’ treatment in our analysis; we show to whom these interventions apply according to NICE guidance in our data supplement. [8] Balen et al say that looking for improved outcomes is irrelevant for this group of patients because ‘without those interventions (which are clearly not “add-ons”) IVF cannot happen.’ NICE, however, in their research recommendations (45 guideline CG156) state the need to ‘determine the long term effects of IVF with or without ICSI in children in the UK.’ [9]
We were pleased to note that Balen et al recognise that the evidence for some interventions is poor. We note that since the publication of our paper the evidence continues to evolve: a new systematic review on time-lapse imaging reported that there is insufficient evidence to support time-lapse imaging compared to conventional methods and there is a need for ‘more well-designed RCTs’ [10] ; a further systematic review, published in May 2017, on strategies to improve fertilisation rates with assisted conception, further stated that ‘adequately powered multicentre randomised trials are required to evaluate these techniques before considering clinical application.’ [11]
We note that Balen et al have said there are shortcomings in our assessments of the quality of evidence for these interventions improving patients’ chances. If the authors can now provide these, we will happily review these and engage in constructive discussion on the emerging findings.
Finally, the use of ad hominem comments provides little benefit to anyone in this debate. Although we recognise the sensitivities and emotions that our work may have evoked amongst the IVF community, and despite widespread concerns over conflicts of interests in the IVF field, we would urge Balen et al to refocus their concerns at the IVF industry itself, and take a lead in utilising their extensive resources to reassure end users, the HFEA and the wider scientific community that their industry’s work is genuinely patient focused and evidence based. We would further suggest that the first step towards this would be to engage with the media, patient groups, policymakers and regulators to address the systemic findings that many interventions that lack good evidence to back them up are being offered to patients.
Carl Heneghan, Ben Goldacre, Elizabeth A Spencer, Jack O’Sullivan, Kamal R Mahtani,
References
[1] Spencer EA, Mahtani KR, Goldacre B, et al Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites. BMJ Open 2016;6:e013940. doi: 10.1136/bmjopen-2016-013940.
[2] Heneghan Carl, Spencer E A, Bobrovitz N, Collins D R J, Nunan D, Plüddemann A et al. Lack of evidence for interventions offered in UK fertility centres BMJ 2016; 355 :i6295
[3] Don’t dismiss conflict-of-interest concerns in IVF, they have a basis https://theconversation.com/dont-dismiss-conflict-of-interest-concerns-i...
[4] Carl Heneghan, Ben Goldacre, Kamal R. Mahtani. Why clinical trial outcomes fail to translate into benefits for patients. Trials, 2017, Volume 18, Number 1, Page 1
[5] Kurt T. Barnhart. Live Birth is the Correct Outcome for Clinical Trials Evaluating Therapy for the Infertile Couple Fertil Steril. 2014 May; 101(5): 1205–1208.
[6] HFEA: Innovation in regulation Feb 2017. http://ifqtesting.blob.core.windows.net/umbraco-website/1796/innovation-...
[7] https://twitter.com/Juliet_Tizzard/status/803511618806104064
[8] http://www.bmj.com/content/bmj/suppl/2016/11/25/bmj.i6295.DC1/henc36462....
[9] Fertility problems: assessment and treatment. Clinical guideline [CG156] Published date: February 2013 Last updated: August 2016 https://www.nice.org.uk/guidance/cg156
[10] Does time-lapse imaging have favorable results for embryo incubation and selection compared with conventional methods in clinical in vitro fertilization? A meta-analysis and systematic review of randomized controlled trials. Chen M, Wei S, Hu J, Yuan J, Liu F.PLoS One. 2017 Jun 1;12(6):e0178720.
[11] Strategies to improve fertilisation rates with assisted conception: a systematic review. Jeve YB, Potdar N, Blower JA, Gelbaya T. Hum Fertil (Camb). 2017 May 26:1-19. doi: 10.1080/14647273.2017.1324182.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following: CH has received grant funding from WHO, the National Institute for Health Research (NIHR), and the NIHR School of Primary Care and occasionally receives expenses for teaching evidence based medicine. He jointly runs the EvidenceLive Conference with BMJ, is editor in chief of the BMJ Evidence-Based Medicine Journal and receives payment as an NHS GP in urgent care. BG has received research funding from the Laura and John Arnold Foundation, the Wellcome Trust, the NIHR, the Health Foundation, and WHO; he also receives personal income from speaking and writing for lay audiences on the misuse of science. KM has received funding from the NIHR and the RCGP for independent research projects. The views expressed here are those of the authors and not necessarily those of any of the affiliated institutions mentioned in the manuscript.
14 June 2017
Carl Heneghan
Professor of EBM
Ben Goldacre, Elizabeth A Spencer, Jack O'Sullivan, Kamal R Mahtani
Centre For Evidence-Based Medicine, Nuffield Department of Primary Care Health Scienes, University of Oxford
Radcliffe Observatory Quarter, Woodstock Road, Oxford. OX2 6GG
@carlheneghan
Some of the conclusions here seem to leave out important data. In particular, the conclusion that occasional drinking increases risk of depression is stated, yet there is no discussion of the discordant finding that "regular" drinking appears to significantly decrease the risk of depression. Without plausible explanatory theories, this kind of discordance does not encourage me to place trust in the findings.
The need to compare with a Baseline
The analysis describes how cases were chosen "where the NHS Pathways software indicated that a patient should be instructed to go to an A&E department" (so dispositions to an emergency department with codes such as Dx02 or Dx03) and how "the call handler told the patient that they would be called back by a GP".
However, as part of the normal process in NHS 111 a further conversation takes place with the patient after the Dx code has been generated during which the specific location of the service that the patient should attend is agreed. As this is done a number of callers are directed to WIC, MIU etc. and to other services. The exact level will depend on various factors, most noticeably the number and location of these alternative services, but analysis from elsewhere of the referrals by call-handlers to Emergency Departments with a time frame of 1 and 4 hours (Dx02 and Dx03) concluded that 15% of those cases go to WIC + MIU 3% to other services, whilst perhaps 7 or 8% were referred to the ambulance service (so may well have been transported to the Emergency Department).
Since, in the study, this conversation with the call-handler was effectively delayedto the later conversation with the GP the comparison should have been with a baseline case, not simply with the nominal NHS Pathways disposition. It seems likely that the impact if the authors had compared with a baseline period using informa...
The need to compare with a Baseline
The analysis describes how cases were chosen "where the NHS Pathways software indicated that a patient should be instructed to go to an A&E department" (so dispositions to an emergency department with codes such as Dx02 or Dx03) and how "the call handler told the patient that they would be called back by a GP".
However, as part of the normal process in NHS 111 a further conversation takes place with the patient after the Dx code has been generated during which the specific location of the service that the patient should attend is agreed. As this is done a number of callers are directed to WIC, MIU etc. and to other services. The exact level will depend on various factors, most noticeably the number and location of these alternative services, but analysis from elsewhere of the referrals by call-handlers to Emergency Departments with a time frame of 1 and 4 hours (Dx02 and Dx03) concluded that 15% of those cases go to WIC + MIU 3% to other services, whilst perhaps 7 or 8% were referred to the ambulance service (so may well have been transported to the Emergency Department).
Since, in the study, this conversation with the call-handler was effectively delayedto the later conversation with the GP the comparison should have been with a baseline case, not simply with the nominal NHS Pathways disposition. It seems likely that the impact if the authors had compared with a baseline period using information available within NHS 111 they would have concluded that some form of management alternative to A&E attendance would have been recommended in perhaps 55% of cases that would otherwise have been sent to the emergency department by the NHS 111 call handler (instead of the 73% quoted)
Selective reporting of costs
The study reports the costs of the saving in attendances at A&E, but it does not include the costs of the attendance at the MIU or WIC nor the cost of the face to face consultation in the out of hours service. This selective reporting of the cost has led to at least one instance (in Pulse) of a saving being reported, when actually the intervention cost more than the saving.
I have read the protocol for The LIFTMOR-M (Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation for Men) trial: protocol for a semi-randomised controlled trial of supervised targeted exercise to reduce risk of osteoporotic fracture in older men with low bone mass and have questions and concerns that I wish your consideration and response:
1. Your protocol calls for 8 months of exposure to the bio Density system. Manufacturers recommendations supported by peer reviewed studies have shown that BMD changes require a minimum of 9 months and many individuals begin to show changes with DEXA at the 11 and 12 month period.
2. Those studies which have shown changes in DEXA as a result of bio Density exposure have done so with subjects who are in osteopenia and not osteoporosis. Your inclusion of males in osteopenia could complicate analysis and conclusions. The best that we have seen is a baseline of those with osteopenia (not getting worse). Also the greater the negative DEXA (ie -3.0, or greater we have seen the greatest change with bio Density exposure). Regression to the mean can be expected.
3. The protocol allows for 2 x per week exposure. The manufacturers recommendations call for once a week.
4. I question if it is appropriate to ask 50 year old men to not perform any form of exercise for 8 or more months while participating in this study. Will the health risk of not exercising be acceptable to the IRB? Other st...
I have read the protocol for The LIFTMOR-M (Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation for Men) trial: protocol for a semi-randomised controlled trial of supervised targeted exercise to reduce risk of osteoporotic fracture in older men with low bone mass and have questions and concerns that I wish your consideration and response:
1. Your protocol calls for 8 months of exposure to the bio Density system. Manufacturers recommendations supported by peer reviewed studies have shown that BMD changes require a minimum of 9 months and many individuals begin to show changes with DEXA at the 11 and 12 month period.
2. Those studies which have shown changes in DEXA as a result of bio Density exposure have done so with subjects who are in osteopenia and not osteoporosis. Your inclusion of males in osteopenia could complicate analysis and conclusions. The best that we have seen is a baseline of those with osteopenia (not getting worse). Also the greater the negative DEXA (ie -3.0, or greater we have seen the greatest change with bio Density exposure). Regression to the mean can be expected.
3. The protocol allows for 2 x per week exposure. The manufacturers recommendations call for once a week.
4. I question if it is appropriate to ask 50 year old men to not perform any form of exercise for 8 or more months while participating in this study. Will the health risk of not exercising be acceptable to the IRB? Other studies have conducted a full fitness assessment and asked the participants to not increase or decrease their exercise protocols and have them monitored weekly.
5. There are many significant issues addressed in your review and protocol and we want you to achieve success with your research. However, we are concerned that you are limiting the results anticipated based upon previous investigations based upon your methodology.
6. If you are interested I would be happy to speak with you about what we have found as well as others who have published in this area.
Jason Conviser, Ph.D., FACSM
Consultant to Performance Health Systems
Please note I have been involved in bio Density research for the past 4 years and have been paid by the manufacturer (Performance Health Systems) to provide research guideance.
The response below should have been posted in January 2017. It responds both to this BMJ Open article and to a related article in The BMJ (http://www.bmj.com/content/355/bmj.i6295). It was posted on bmj.com on January 18 2017 but failed to be replicated within BMJ Open. We apologise for this. The authors have been asked to respond.
Re: Lack of evidence for interventions offered in UK fertility centres.
We are writing to express our concern regarding the papers by Heneghan et al, (2016) and Spencer et al (2016) owing to their lack of scientific robustness.
We would like to state at the outset that we oppose the provision of procedures or treatments that do not have a scientific basis and we welcome the initiative by the Human Fertilisation and Embryology Authority (HFEA), which has been endorsed by the British Fertility Society (BFS), to introduce a grading scheme for “add-ons”.
Spencer, Heneghan and colleagues have unfortunately obscured their important message by mixing various categories of treatment, not all of which come under the category of “add-ons”. Indeed, a number are accepted components of routine treatment. The papers have grouped together three categories of care: (i) necessary investigations (e.g. assessment of ovarian reserve, which is vital in determining correct dosage of ovarian stimulation drugs to optimise outcome and ensure patient safety), (ii) essential treatments (e.g. surgical sperm retrieval) and (iii) interventions that can be termed “add-ons” - namely an addition to a pathway of care, whether as an additional drug or therapeutic procedure. Many of the items identified have a clearly defined role in specific situations; e.g. for a man with a physical blockage sperm has to be extracted surgically, frozen an...
Re: Lack of evidence for interventions offered in UK fertility centres.
We are writing to express our concern regarding the papers by Heneghan et al, (2016) and Spencer et al (2016) owing to their lack of scientific robustness.
We would like to state at the outset that we oppose the provision of procedures or treatments that do not have a scientific basis and we welcome the initiative by the Human Fertilisation and Embryology Authority (HFEA), which has been endorsed by the British Fertility Society (BFS), to introduce a grading scheme for “add-ons”.
Spencer, Heneghan and colleagues have unfortunately obscured their important message by mixing various categories of treatment, not all of which come under the category of “add-ons”. Indeed, a number are accepted components of routine treatment. The papers have grouped together three categories of care: (i) necessary investigations (e.g. assessment of ovarian reserve, which is vital in determining correct dosage of ovarian stimulation drugs to optimise outcome and ensure patient safety), (ii) essential treatments (e.g. surgical sperm retrieval) and (iii) interventions that can be termed “add-ons” - namely an addition to a pathway of care, whether as an additional drug or therapeutic procedure. Many of the items identified have a clearly defined role in specific situations; e.g. for a man with a physical blockage sperm has to be extracted surgically, frozen and used in an IVF cycle combined with intra-cytoplasmic sperm injection (ICSI). For this group of patients, without those interventions (which are clearly not “add-ons”) IVF cannot happen and looking for improved outcomes is irrelevant. Therefore, the papers are inherently flawed as the basis upon which they are structured is clinically and scientifically unsound.
The BMJ disregarded key points made by one of the referees which should have alerted the authors to fundamental flaws in their enquiry: Quoting Dr Avery’s review “For this paper to have the intended impact, the authors need to decide whether to include all procedures for which centres are charging a fee, or whether as the title suggests, they are going to stick to add-ons, specifically those for which claims of increased live birth rates are made.……., in its current form it [the paper] could easily be dismissed by those it targets as having been written by those with no understanding of the field or the technology ….” It is clear that no specialists in reproductive medicine were involved which is why the authors misunderstood and misinterpreted their task. To quote one co-author this is a clear example of “Bad Science” (Goldacre, 2009).
We are fully aware there may be “add-ons” that are not evidence-based, either because the research has not yet been carried out, or because they have been found to be ineffective (Harper et al 2017). The use of intralipid is one such example. This has been clearly stated by the BFS (Nardo et al 2014) and Royal College of Obstetricians and Gynaecologists (RCOG 2016) and so it is perfectly legitimate to criticise a clinic for offering intralipid. However, when it is only 3 clinics (4%) offering this intervention on their websites, it should be clearly stated that this is not mainstream practice or representative of the whole sector.
Treatments that appear more frequently on websites, such as ICSI and blastocyst culture, and the “add-ons” such as embryoglue and endoscratch do have an evidence base. We can present an analysis of each of the 41 items which clarifies the evidence for many and against some. However, it is important to recognise that, although live birth rate is the key outcome measure recommended by the HFEA and something patients need to know, using live birth as the sole indicator of an evidence base oversimplifies a hugely complex process and fails to recognise the significant scientific research underlying decisions to bring treatments into clinical practice.
We are under no illusion that there are sections of the sector that are commercially driven and offering invalidated, costly “add-ons”. Clinics are inspected and called to account by the HFEA, resulting in greater regulation of the fertility sector than any other area of medicine. Furthermore, the HFEA inspectors examine all written information and consent forms that are given to patients, which will always be a truer reflection of clinical practice than the summaries on websites. In the conclusion of the publications, the authors’ own criteria were not fulfilled. The authors were asked “to carry out an independent review of the evidence for fertility treatments additional to IVF”, which they did not do. They only looked at websites and took no account of information provided to or understood by patients at consultations or in the clinics’ written literature. Whether patient literature should be referenced is an interesting concept, as not even that produced by NICE includes references. Nonetheless, we are absolutely clear that websites must provide accurate information that does not mislead patients.
Had the authors sought the input of specialists in reproductive medicine they would have been able to write scientifically sound papers and contributed to a debate (and associated work by the HFEA and BFS) already underway in the sector. To place an article in the public domain that is highly inaccurate and misrepresents the fertility sector is both misleading and deeply unhelpful to patients.
We strongly believe that these papers should not have been published in their current form. Whilst we welcome scrutiny that contributes accurate analysis and informs the mechanisms by which future advances should be brought into clinical practice, our concern is that this should be conducted in a scientifically robust manner that provides clarity to the topic. Given the rapid advances in reproductive medicine, such work is vital and contributes to the natural evolution of the sector’s regulatory machinery. It is important that we work together to promote ethical and innovative patient care.
The key objectives of the BFS are to promote high quality clinical practice and high quality research. To this end, we would be happy to collaborate with the authors to ensure that their research results in valid conclusions.
Yours sincerely
Adam Balen, MD, DSc, FRCOG.
Professor of Reproductive Medicine and Surgery, Leeds &
Chair of The British Fertility Society (BFS).
Lesley Regan, MD DSc FRCOG FACOG
President of the RCOG,
Professor& Head of Department of Obstetrics and Gynaecology, Imperial College & St Mary’s Hospital,London
Sue Avery PhD FRCPath PGDipLaw - referee of the original paper.
Consultant Embryologist & Director of Birmingham Women’s Fertility Centre.
Peter Braude OBE, FRCOG, FRSB, FMedSci
Emeritus Professor of Obstetrics and Gynaecology, King's College London
Ian Cooke FMedSci, FRCOG, FRANZCOG (Hon.)
Former Chairman, former President of the British Fertility Society and current Chairman of Trustees
Director of Education, International Federation of Fertility Societies, 2004-2011
Emeritus Professor, University of Sheffield
Grace Dugdale BSc, MA.
Reproductive biologist, London
Susan Seenan, Chief Executive, Fertility Network UK
(The UK support organisation for people with infertility)
Yacoub Khalaf MSc MD FRCOG
Consultant Gynaecologist & Sub-Specialist in Reproductive Medicine and Surgery,
Director of the Assisted Conception Unit & Centre for Pre-implantation Genetic Diagnosis, Guys & St Thomas’ Hospital, London
Member of The HFEA.
Anthony J Rutherford FRCOG
Consultant in Reproductive Medicine & Gynaecological Surgery, Leeds.
Past Chair of The British Fertility Society.
Member of The HFEA.
Peter R. Brinsden MB BS FRCOG
Past-President of the British Fertility Society
Former Medical Director Bourn Hall clinic, Cambridge.
Tim Child MA MD MRCOG
Associate Professor, University of Oxford
Medical Director, Oxford Fertility.
Henry Leese PhD, FRCOG
Professor Emeritus Reproductive Biology, Hull York Medical School
President of The British Fertility Society.
Alison Murdoch MD, FRCOG
Professor of Reproductive Medicine, Newcastle &
Past Chair of The British Fertility Society.
Allan Pacey MBE, PhD, FRCOG ,
Professor of Andrology, Sheffield University.
Past Chair of The British Fertility Society.
Mark Hamilton MD FRCOG
Consultant in Reproductive Medicine, Aberdeen Maternity Hospital.
Past Chair of The British Fertility Society.
David Adamson, MD, FRCSC, FACOG, FACS
Chair, International Committee Monitoring Assisted Reproduction Technology
Past President, American Society for Reproductive Medicine
Bart CJM Fauser, MD, PhD,
Professor of Reproductive Medicine & Gynecology, Utrecht, The Netherlands
Chair WHO Global Guidelines Taskforce for the Management of Infertility.
And (in alphabetical order)
Hossam Abdalla MD, FRCOG
Director & Person Responsible of the Lister Fertility Clinic, London
Past Member of The HFEA.
Ian Aird MB ChB, FRCOG
Consultant Gynaecologist and Person Responsible
Gateshead Fertility Unit, Queen Elizabeth Hospital Gateshead
Valentine Akande PhD MRCOG
Lead Clinician & Person Responsible
Bristol Centre for Reproductive Medicine
Richard A Anderson PhD, FRCOG
Elsie Inglis Professor of Clinical Reproductive Sciences
Head of Section, Obstetrics and Gynaecology, University of Edinburgh,
MRC Centre for Reproductive Health
Harish Bhandari MD MRCOG
Subspeciality Trainee in Reproductive Medicine, Newcastle
N. Ellissa Baskind MD MRCOG
Subspeciality Trainee in Reproductive Medicine, Leeds Teaching Hospitals
Joshua D Blazek PhD
CooperGenomics, Genesis Genetics
Virginia N Bolton MA, PhD
Consultant Embryologist, Honorary Senior Lecturer, KCL
Assisted Conception Unit, Guy's & St Thomas’ Hospital,
Treasurer of The British Fertility Society
Rachel Cutting MBE, MSc
Consultant Embryologist, Sheffield University Hospitals
Former Chair of The Association of Clinical Embryologists
Dr Melanie Davies MA MRCP FRCOG
Consultant in Reproductive Medicine, HFEA Person Responsible, University College London Hospitals
C Janine Elson MD, FRCOG,
Consultant Gynaecologist and Subspecialist in Reproductive Medicine and Surgery,
Associate Medical Director CARE Fertility Group
Professor Simon Fishel PhD (Cantab) FRSB
Founder, President and Head of R&D for CARE Fertility.
Darren K Griffin PhD, DSc, FRSA, FRSB, FRCPath
Professor of Genetics, School of Biosciences, University of Kent
President of the International Chromosome and Genome Society
Jamie Grifo MD PhD
Professor and Director New York University Fertility Center, New York, USA
Stephen Harbottle PhD
Consultant Clinical Embryologist,
HFEA Person Responsible, Cambridge University Fertility Centre
Chair of the Association of Clinical Embryologists
James Hopkisson MBBS MD MRCOG
Associate Professor, & Sub Specialist in Reproductive Medicine, Nottingham University Hospital; Person Responsible Nurture Fertility
Kanna Jayaprakasan MD MRCOG PhD
Hon. Associate Professor & Subspecialist in Reproductive Medicine,
HFEA Person Responsible, Derby Fertility Unit, Royal Derby Hospital, Derby.
Jason Kasraie PhD
Consultant Embryologist & Andrologist
HFEA Person Responsible, Shropshire & Mid-Wales Fertility Centre
Chair Elect of the Association of Clinical Embryologists
Charles Kingsland MD FRCOG
Professor of Reproductive Medicine
Liverpool Women's Hospital
Jackson C Kirkman-Brown MBE PhD,
Reader & NIHR/HEE Senior Clinical Fellow in Healthcare Science, College of Medical & Dental Sciences, The University of Birmingham.
Stuart Lavery MBBCh MSc MRCOG
Consultant Gynaecologist, Person Responsible IVF Unit, Hammersmith Hospital
Honorary Senior Lecturer, Imperial College, London.
Christine Leary BSc, PhD, FRCPath
Consultant Embryologist,
The Hull IVF Unit, Hull Royal Infirmary
Sheena E. M. Lewis BSc PhD CBiol FRSB
Emeritus Professor Andrology,
Queen's University Belfast,
Chair British Andrology Society,
Member of HFEA SCAAC Committee
Gillian Lockwood FRCOG DPhil MA (Oxon)
Medical Director, Midland Fertility
Jane MacDougall FRCOG MD MEd
Consultant Reproductive Medicine, Cambridge University Hospitals,
Head of School, EOE Postgraduate School Obstetrics & Gynaecology, Director of Studies Clinical Medicine, Newnham College Cambridge
Alison McTavish RGN, RN
Manager Aberdeen Fertility Centre,
Past Secretary of BRITISH FERTILITY SOCIETY and Chair of Senior Infertility Nurses Group
Enda McVeigh FRCOG
Consultant in Reproductive Medicine, Oxford
Nick S. Macklon MD, FRCOG
Professor of Obstetrics and Gynaecology
University of Southampton
Scientific Director, Complete Fertility Centre.
Steve Maguiness MD, FRCOG
Consultant in Reproductive Medicine, Hull Royal Infirmary
Abha Maheshwari MBBS, MD, FRCOG
Person Responsible & Clinical Lead Reproductive Medicine, Aberdeen Fertility Centre
Raj Mathur MD, FRCOG
Clinical Lead for Reproductive Medicine, Central Manchester NHS Foundation Trust;
Hon. Senior Lecturer, University of Manchester
Dimitrios Mavrelos MD, MRCOG
Consultant in Reproductive Medicine, University College London Hospital
James Nicopoullos BSc MBBS MD MRCOG DFFP
Consultant Gynaecologist, Subspecialist in Reproductive Medicine & Surgery, Lister Fertility Clinic, London
David Polson MD FRCOG
Medical Director, Manchester Fertility
Nick Raine-Fenning PhD, MRCOG
Consultant in Reproductive Medicine & Associate Professor, Nottingham.
PD Dr. med. habil. Andreas G. Schmutzler
Gynecologist, Specialist in Reproductive Medicine and Lawyer, Lecturer
Kiel University for Gynecology, Reproductive Medicine and Ethics
Jane Stewart, MD, FRCOG.
Consultant in Reproductive Medicine, Newcastle
Secretary of The British Fertility Society
Isabel Traynor BA(hons) RGN,
Nurse Representative British Fertility Society.
Geoffrey H Trew FRCOG.
Consultant in Reproductive Medicine & Surgery, Hammersmith Hospital, London.
Attila Vereczkey, MD, MA
Medical Director of Versys Clinics, Human Reproduction Institute, Budapest Hungary
President of the Hungarian Human Reproduction Society
President of International Society of Periconceptional Medicine
Simon Wood MD, FRCOG.
Consultant in Reproductive Medicine, Countess of Chester NHS Foundation Trust
Ephia Yasmin MD, MRCOG
Consultant Obstetrician and Gynaecologist. Sub specialist in Reproductive Medicine.
Clinical Lead, Reproductive Medicine Unit University College London Hospital, London
References
Goldacre B. Bad Science by, 2009, Harper Perennial ISBN: 9780007284870.
Harper, J, Jackson, E, Sermon, K, Aitken RJ, Harbottle, S, Mocanu, E, Hardarson, T, Mathur, R, Viville, S, Vail, A, Lundin, K Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions? Human Reproduction (2017 in press).
Heneghan C, Spencer EA, Bobrovitz N, Collins D R J, Nunan D, Plüddemann A, Gbinigie OA, Onakpoya I, O’Sullivan J, Rollinson A, Tompson A, Goldacre B, Mahtani K R. Lack of evidence for interventions offered in UK fertility centres. BMJ 2016; 355 doi: http://dx.doi.org/10.1136/bmj.i6295)
Nardo LG, El-Toukhy T, Stewart J, Balen AH, Potdar N. Adjuvants in IVF: evidence for good clinical practice. On behalf of the British Fertility Society P&P Committee. Human Fertiity, 2014; DOI:10.3109/14647273.2015.985454.
RCOG. The role of natural killer cells in human fertility. RCOG Scientific Impact Paper, number 52, November 2016.
Spencer EA, Mahtani K R, Goldacre B, Heneghan C. Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites. BMJ 2016; 355:i6295 doi:10.1136/bmj.6295.
I read the article written by Rajkumar et al. [1] with great interest and appreciate the efforts taken by the investigators to screen the prevalence of COPD in different age groups in India. However, there are two aspects on which I would like to make some comments. The authors have stated “Globally COPD was the fourth leading cause of death (5.1%) in 2004 and is projected to occupy the third position (8.6%) in 2030”, I assume that the statistics are quite overestimated. Mathers and Loncar (2006) [2], provided a more comprehensive picture about the projected scenario of COPD globally and they concluded that COPD is at present the 5th leading cause of mortality and morbidity globally and is likely to step up to 4th position by 2030 with an increment of 160%. I think that the authors need to consider the fact. Secondly, the authors might have missed that recently, Desai and colleagues (2016) have published spirometry prediction equations for Indian adults residing in the western parts of India [3]. The equations have successfully overcome a long-awaited aspiration for standard prediction models in Indian perspective and could be used as Indian standard. Most of the existing prediction models such as the global lung function equations developed by Quanjer et al. (2012) [4] which were developed for Europeans either under-diagnose or over-diagnose the disease, hence I think the newly published models would serve the purpose.
I read the article written by Rajkumar et al. [1] with great interest and appreciate the efforts taken by the investigators to screen the prevalence of COPD in different age groups in India. However, there are two aspects on which I would like to make some comments. The authors have stated “Globally COPD was the fourth leading cause of death (5.1%) in 2004 and is projected to occupy the third position (8.6%) in 2030”, I assume that the statistics are quite overestimated. Mathers and Loncar (2006) [2], provided a more comprehensive picture about the projected scenario of COPD globally and they concluded that COPD is at present the 5th leading cause of mortality and morbidity globally and is likely to step up to 4th position by 2030 with an increment of 160%. I think that the authors need to consider the fact. Secondly, the authors might have missed that recently, Desai and colleagues (2016) have published spirometry prediction equations for Indian adults residing in the western parts of India [3]. The equations have successfully overcome a long-awaited aspiration for standard prediction models in Indian perspective and could be used as Indian standard. Most of the existing prediction models such as the global lung function equations developed by Quanjer et al. (2012) [4] which were developed for Europeans either under-diagnose or over-diagnose the disease, hence I think the newly published models would serve the purpose.
References:
1. Rajkumar P, Pattabi K, Vadivoo S, Bhome A, Brashier B, Bhattacharya P, Mehendale SM. A cross-sectional study on prevalence of chronic obstructive pulmonary disease (COPD) in India: rationale and methods. BMJ Open 2017;7:e015211. doi:10.1136/bmjopen-2016-015211
2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3: e442.
3. Desai U, Joshi JM, Chhabra SK, Rahman MU. Prediction equations for spirometry in adults in western India. Indian J Tuberc. 2016;63(3):176-182. doi: 10.1016/j.ijtb.2016.08.005.
4. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40:1324–43.
As the two comments posted on PubMed for the cited article by Dr Ravnskov et al clearly state, there are several major shortcomings in the design and analysis of their meta-analysis. In addition, benefits of statins in reducing risk of myocardial infarction in older age patients without cardiovascular disease have been shown in several randomized trials.
Our analysis adds to the literature by providing an insight on how use of palm oil for cooking (as opposed to sunflower oil) may worsen lipid profiles in a population from a low-income country with implications for cardiovascular disease. As we have discussed, a large case-control study has already shown an association between palm oil use and non-fatal myocardial infarction.
This fascinating paper has a serious flaw; the exclusion of all studies with treatment-as-usual (TAU) comparison conditions. The authors justify this decision by stating that TAU is not standardized and cannot be considered an inactive condition. However, the difference between TAU and two included control conditions (wait-list and no care) may be predominantly semantic. Patients randomized to no care or wait-list cannot be forbidden from continuing to participate in the healthcare system and may receive exactly the treatments that they would usually receive if they were not enrolled in a clinical trial; that is, treatment as usual. No care and wait-list may not be any more standardized than TAU. Furthermore, TAU is what happens in the real world. Given the state of the mental health infrastructure in many countries, behavioural treatments are often compared against TAU to see if they are beneficial compared to what the patient would receive otherwise.
I have read the authors’ report on the investigation of data collection mode effects during administration of a three-item patient-reported patient-centered communication measure with interest. While I greatly appreciate the work the authors invested in the study, I think one of their major conclusions is not supported by the reported analyses. It is repeatedly stated throughout the manuscript that the relative clinician performance rankings were stable across the different data collection modes. However, the analytic strategy described in the Methods section, the perfectly identical distances between physicians (on the logit-scale) across modes in Figure 1, and the detailed results made available in the Supplementary Appendices suggest that they included the clinician identifiers as main effects in the analyses without specifying an interaction term between data collection mode and physician identifiers. This means that the ranking of (and even equal metric distance in logit units between) clinicians was restricted to be identical across all levels of the covariates, including administration mode, by the statistical model. In other words, the stable clinician ranking was rather a non-falsifiable assumption than a finding of the analyses.
Show MoreThis does not mean that the authors’ conclusion is necessarily wrong, only that the performed analyses did not check the hypothesis of constant clinician ranking across modes as intended. Additional analyses may show that this hypot...
To The Editor, BMJ
Dear Dr Godlee
Balen et al have responded to our papers. [1,2] In our BMJ open paper we systematically identified 276 claims of benefit relating to 41 different fertility interventions and 16 published references were cited 21 times on 13 of the 74 websites we searched.[1] In our BMJ analysis paper, we systematically examined the evidence for ‘38 additional fertility interventions’ and found evidence of improvements in live birth rates for only five interventions. We used standard critical appraisal techniques (as detailed in our paper) to explore the quality of these studies. We identified that for all five of these interventions the studies had methodological problems, raising uncertainty about the significance of the results. This is a serious issue for patients, public health, public trust, and regulators.
Balen et al suggest that our evidence review included - and found evidence lacking for - things which are not “add-ons”. We classified ‘add-ons’ in the BMJ analysis article in response to peer review where the issue was discussed (see online peer review comments).
Peer review comment: ‘The methodology has led them to five interventions for which there may be some evidence of improvement in live birth rates. One of these is intrauterine insemination in a natural cycle. This is an alternative treatment, rather than an “add-on”, and usually not one applied to the population who require IVF, and certainly not one intended to...
Show MoreSome of the conclusions here seem to leave out important data. In particular, the conclusion that occasional drinking increases risk of depression is stated, yet there is no discussion of the discordant finding that "regular" drinking appears to significantly decrease the risk of depression. Without plausible explanatory theories, this kind of discordance does not encourage me to place trust in the findings.
The need to compare with a Baseline
Show MoreThe analysis describes how cases were chosen "where the NHS Pathways software indicated that a patient should be instructed to go to an A&E department" (so dispositions to an emergency department with codes such as Dx02 or Dx03) and how "the call handler told the patient that they would be called back by a GP".
However, as part of the normal process in NHS 111 a further conversation takes place with the patient after the Dx code has been generated during which the specific location of the service that the patient should attend is agreed. As this is done a number of callers are directed to WIC, MIU etc. and to other services. The exact level will depend on various factors, most noticeably the number and location of these alternative services, but analysis from elsewhere of the referrals by call-handlers to Emergency Departments with a time frame of 1 and 4 hours (Dx02 and Dx03) concluded that 15% of those cases go to WIC + MIU 3% to other services, whilst perhaps 7 or 8% were referred to the ambulance service (so may well have been transported to the Emergency Department).
Since, in the study, this conversation with the call-handler was effectively delayedto the later conversation with the GP the comparison should have been with a baseline case, not simply with the nominal NHS Pathways disposition. It seems likely that the impact if the authors had compared with a baseline period using informa...
I have read the protocol for The LIFTMOR-M (Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation for Men) trial: protocol for a semi-randomised controlled trial of supervised targeted exercise to reduce risk of osteoporotic fracture in older men with low bone mass and have questions and concerns that I wish your consideration and response:
Show More1. Your protocol calls for 8 months of exposure to the bio Density system. Manufacturers recommendations supported by peer reviewed studies have shown that BMD changes require a minimum of 9 months and many individuals begin to show changes with DEXA at the 11 and 12 month period.
2. Those studies which have shown changes in DEXA as a result of bio Density exposure have done so with subjects who are in osteopenia and not osteoporosis. Your inclusion of males in osteopenia could complicate analysis and conclusions. The best that we have seen is a baseline of those with osteopenia (not getting worse). Also the greater the negative DEXA (ie -3.0, or greater we have seen the greatest change with bio Density exposure). Regression to the mean can be expected.
3. The protocol allows for 2 x per week exposure. The manufacturers recommendations call for once a week.
4. I question if it is appropriate to ask 50 year old men to not perform any form of exercise for 8 or more months while participating in this study. Will the health risk of not exercising be acceptable to the IRB? Other st...
The response below should have been posted in January 2017. It responds both to this BMJ Open article and to a related article in The BMJ (http://www.bmj.com/content/355/bmj.i6295). It was posted on bmj.com on January 18 2017 but failed to be replicated within BMJ Open. We apologise for this. The authors have been asked to respond.
To The Editor, BMJ
Dear Dr Godlee
Re: Lack of evidence for interventions offered in UK fertility centres.
We are writing to express our concern regarding the papers by Heneghan et al, (2016) and Spencer et al (2016) owing to their lack of scientific robustness.
We would like to state at the outset that we oppose the provision of procedures or treatments that do not have a scientific basis and we welcome the initiative by the Human Fertilisation and Embryology Authority (HFEA), which has been endorsed by the British Fertility Society (BFS), to introduce a grading scheme for “add-ons”.
Spencer, Heneghan and colleagues have unfortunately obscured their important message by mixing various categories of treatment, not all of which come under the category of “add-ons”. Indeed, a number are accepted components of routine treatment. The papers have grouped together three categories of care: (i) necessary investigations (e.g. assessment of ovarian reserve, which is vital in determining correct dosage of ovarian stimulation drugs to optimise outcome and ensure patient safety), (ii) essential treatments (e.g. surgical sperm retrieval) and (iii) interventions that can be termed “add-ons” - namely an addition to a pathway of care, whether as an additional drug or therapeutic procedure. Many of the items identified have a clearly defined role in specific situations; e.g. for a man with a physical blockage sperm has to be extracted surgically, frozen an...
Show MoreI read the article written by Rajkumar et al. [1] with great interest and appreciate the efforts taken by the investigators to screen the prevalence of COPD in different age groups in India. However, there are two aspects on which I would like to make some comments. The authors have stated “Globally COPD was the fourth leading cause of death (5.1%) in 2004 and is projected to occupy the third position (8.6%) in 2030”, I assume that the statistics are quite overestimated. Mathers and Loncar (2006) [2], provided a more comprehensive picture about the projected scenario of COPD globally and they concluded that COPD is at present the 5th leading cause of mortality and morbidity globally and is likely to step up to 4th position by 2030 with an increment of 160%. I think that the authors need to consider the fact. Secondly, the authors might have missed that recently, Desai and colleagues (2016) have published spirometry prediction equations for Indian adults residing in the western parts of India [3]. The equations have successfully overcome a long-awaited aspiration for standard prediction models in Indian perspective and could be used as Indian standard. Most of the existing prediction models such as the global lung function equations developed by Quanjer et al. (2012) [4] which were developed for Europeans either under-diagnose or over-diagnose the disease, hence I think the newly published models would serve the purpose.
References:
Show More1. Rajkumar P, Pattabi K, Va...
As the two comments posted on PubMed for the cited article by Dr Ravnskov et al clearly state, there are several major shortcomings in the design and analysis of their meta-analysis. In addition, benefits of statins in reducing risk of myocardial infarction in older age patients without cardiovascular disease have been shown in several randomized trials.
Our analysis adds to the literature by providing an insight on how use of palm oil for cooking (as opposed to sunflower oil) may worsen lipid profiles in a population from a low-income country with implications for cardiovascular disease. As we have discussed, a large case-control study has already shown an association between palm oil use and non-fatal myocardial infarction.
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