The clinical evidence we produce which impacts the care we deliver to patients must have the highest standards. Unlike biomedical evidence, the evidence behind our treatments, risk factors and diagnostic tests should be relevant to the patients and clinicians who practice at the coal-face and real-world of General Practice and our hospitals.
We may have had 250,000 'peer-reviewed' articles relating to COVID-19 (whatever credibility that affords), but allowing biomedical assumptions to creep into guidelines and direct patient care, is taking a step backwards in evidence-based practice. COVID saw a multitude of 'experts' give their opinion freely in the media and on social media platforms, based on biomedical ‘evidence’, on opinion, through the platforming of academic-status and on dubious case-studies. This was self-evidently un-scientific, and arguably has set science back. Yet this article seems to advance the notion that this evidence should impact patient care.
So much has to be done to enable EBM to flourish- yet this article will likely set EBM back. The evidence underpinning our treatments should be quantifiable in absolute terms, and the uncertainties and conflicts of interests (COIs) acknowledged. The evidence behind our risk factors characterised in absolute terms, within the context of confounders and biases from observational studies. Our diagnostic tests should be understood within the context of odds and post-test probability. O...
The clinical evidence we produce which impacts the care we deliver to patients must have the highest standards. Unlike biomedical evidence, the evidence behind our treatments, risk factors and diagnostic tests should be relevant to the patients and clinicians who practice at the coal-face and real-world of General Practice and our hospitals.
We may have had 250,000 'peer-reviewed' articles relating to COVID-19 (whatever credibility that affords), but allowing biomedical assumptions to creep into guidelines and direct patient care, is taking a step backwards in evidence-based practice. COVID saw a multitude of 'experts' give their opinion freely in the media and on social media platforms, based on biomedical ‘evidence’, on opinion, through the platforming of academic-status and on dubious case-studies. This was self-evidently un-scientific, and arguably has set science back. Yet this article seems to advance the notion that this evidence should impact patient care.
So much has to be done to enable EBM to flourish- yet this article will likely set EBM back. The evidence underpinning our treatments should be quantifiable in absolute terms, and the uncertainties and conflicts of interests (COIs) acknowledged. The evidence behind our risk factors characterised in absolute terms, within the context of confounders and biases from observational studies. Our diagnostic tests should be understood within the context of odds and post-test probability. Our guidelines currently inhibit the practice of EBM, without such information.
By providing credibility to case studies, mechanistic evidence and expert opinion as a reliable predictor of exposure to outcome, I fear a Trojan horse of 'science-experts' driving un-evidenced practices into clinical medicine will happen- at huge risk to patient care, shared decision-making, conflicts of interest and healthcare costs.
Not a good day for EBM.
Airborne transmission and inhalation, of SARS-CoV-2 is recognized by international public health agencies (Addleman et al. 2021) from both short- and long-range aerosol transmission (Tang et al. 2021).
When comparing filtering face piece (FFP) respirators, with a surgical (medical) masks, for protection against an inhalable (ISO 7708) airborne virus such as SARS-CoV-2, “EQUIPOISE” a central tenet for conducting a randomised control trial (RCT), does not exist. The futility of using a RCT is analogous to carrying out a study in a construction site for hard hats or seat belts in a passenger vehicle. FFP respirators used in Canada are selected and used in accordance with CAN/CSA-Z94.4-18 (Selection, use, and care of respirators). Specifications are provided in CSA Z94.4.1:21 (Performance of filtering respirators).
At least two international studies using RCT have been initiated since the start of the COVID-19 pandemic.
a) United Kingdom: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 for healthcare workers (The funding committee did not recommend funding).
b) Canada, multi-centre: where nurses are randomized to either use of a medical mask or to a fit-tested N95 respirator when providing care for patients with febrile respiratory illness.
The findings from a poorly designed RCT may also be used as improper and biased rationale to downgrade respirator (masks...
Airborne transmission and inhalation, of SARS-CoV-2 is recognized by international public health agencies (Addleman et al. 2021) from both short- and long-range aerosol transmission (Tang et al. 2021).
When comparing filtering face piece (FFP) respirators, with a surgical (medical) masks, for protection against an inhalable (ISO 7708) airborne virus such as SARS-CoV-2, “EQUIPOISE” a central tenet for conducting a randomised control trial (RCT), does not exist. The futility of using a RCT is analogous to carrying out a study in a construction site for hard hats or seat belts in a passenger vehicle. FFP respirators used in Canada are selected and used in accordance with CAN/CSA-Z94.4-18 (Selection, use, and care of respirators). Specifications are provided in CSA Z94.4.1:21 (Performance of filtering respirators).
At least two international studies using RCT have been initiated since the start of the COVID-19 pandemic.
a) United Kingdom: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 for healthcare workers (The funding committee did not recommend funding).
b) Canada, multi-centre: where nurses are randomized to either use of a medical mask or to a fit-tested N95 respirator when providing care for patients with febrile respiratory illness.
The findings from a poorly designed RCT may also be used as improper and biased rationale to downgrade respirator (masks) to surgical masks (Greenhalgh et al. 2022).
A subject should be enrolled in an RCT only if there is true uncertainty (equipoise) about which of the trial arms is likely to benefit the participants (Fries & Krishan 2004), otherwise the study may be unethical. Other study methodology should not be discounted and EBM+ provides a way forward.
An “observational” cohort study from Switzerland, covering 2919 HCWs spread over 7 health care networks, demonstrated 21% of infections occurred for HCWs using respirator masks compared with 35% for those using surgical/mixed masks (Dorr et al. 2022). Infections may have been greatly reduced if there was a solid respiratory protection program in place, which is not clear from the information provided.
An observational study by Ferris et al. 2021, demonstrated how important it is for HCWs caring for patients with COVID-19, whether aerosol generating procedures (AGPs) were undertaken or not to use respirators and not surgical masks.
A cross-sectional prospective study from Finland clearly demonstrated that respirators are superior (Oksanen et al. 2021). A systematic review where eight studies (9164 participants) were included after screening 153 articles followed by a meta-analysis (Collins et al. 2021).
Healthcare workers (at risk) need respiratory protection in accordance with international standards; plus, good ventilation, and administrative controls, to limit their risk of exposure to infected co-workers and patients. Reduced infection lowers the risk of work overload, moral injury and household and community transmission.
The Canada, Quebec’s court decision, ensures that all health-care professionals are provided an N95 respirator immediately when a resident or patient is suspected to be infected with COVID-19 (Hedges et al 2021, Justice Philippe Bouvier – court decision 2021).
“Thousands of lives were likely lost as a result of what was incorrectly claimed to be an evidence-based approach dismissing or downgrading mechanistic evidence, overvaluing the findings from poorly designed or irrelevant RCTs, and advocating for inaction where RCT evidence was lacking” (Greenhalgh 2022, p.1).
All relevant disciplines must be engaged (e.g., engineers, occupational hygienists, aerosol scientists, social and behavioural scientists, epidemiologists) in the research so that “up to date” and mechanistic evidence (Greenhalgh et al. 2022a, table 2) is incorporated in important policy decision making.
EBM+ provides a framework moving forward at this critical time.
References
Addleman S, Leung V, Asadi, L, Sharkawy, A, McDonald J 2021, “Mitigating airborne transmission of SARS-CoV-2”. Canadian Medical Association Journal (CMAJ), CMAJ July 05, 2021 193 (26) E1010-E1011; DOI: Retrieved 9 August 2022: https://doi.org/10.1503/cmaj.210830
Canadian Aerosol Transmission Coalition (CATC), January 4 2021, “There is still time to address aerosol transmission of COVID-19”, correspondence with Canadian and Provincial, Public Health Agency of Canada (PHAC), premiers and ministers. Retrieved 9 August 2022: https://www.aerosoltransmissioncoalition.ca/_files/ugd/cdecb4_0c05d1fea9...
Canadian CSA Group CAN/CSA-Z94.4-18 Selection, use, and care of respirators. Retrieved 9 August 2022: https://www.csagroup.org/store/product/CAN%25100CSA-Z94.4-18/
Canadian CSA Group CSA Z94.4.1, Performance of filtering respirators. Retrieved 9 August 2022: https://www.csagroup.org/store/product/2429470/
Collins AP, Service BS, Gupta S, Mubarak, N, Zeini, IM, Osbahr DC, Romeo AA 2021, N95 respirator and surgical mask effectiveness against respiratory viral illnesses in the healthcare setting: A systematic review and meta-analysis. J Am Coll Emerg Physicians Open .2021 Oct 28;2(5):e12582. doi: 10.1002/emp2.12582. eCollection 2021 Oct. Retrieved 9 August 2022: https://pubmed.ncbi.nlm.nih.gov/34746923/
Dörr, T Sabine, Haller TS, Müller MF, Friedel A, Vuichard D, Kahlert CR, Kohler P 2022, Risk of SARS-CoV-2 Acquisition in Health Care Workers According to Cumulative Patient Exposure and Preferred Mask Type, JAMA Network Open, Infectious Diseases, Open. 2022;5(8). August 15 2022.
Ferris M, Ferris R, Workman C, O’Connor E, Enoch DA, Goldesgeyme E, Quinnell N, et al. 2021, “ Efficacy of FFP3 respirators for prevention of SARS-CoV-2 infection in healthcare workers”, Epidemiology and Global Health | Microbiology and Infectious Disease, eLife 2021;10:e71131. DOI: Retrieved 9 August 2022: https://doi.org/10.7554/eLife.71131
Fries JF, Krishnan E 2004, Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development, Arthritis Res Ther. 2004;6(3):R250-5. doi: 10.1186/ar1170. Epub 2004 Mar 18. Retrieved 9 August 2022. https://pubmed.ncbi.nlm.nih.gov/15142271/
Greenhalgh T, Kane B, Reicher S 2022, “Downgrade your mask before entering”—a dangerous NHS policy at a critical public health juncture”. BMJ 2022;378:o1929. Retrieved 9 August 2022: https://www.bmj.com/content/378/bmj.o1929
Greenhalgh T, Fisman D, Cane DJ, et al. 2022a. “Adapt or die: how the pandemic made the shift from EBM to EBM+ more urgent” BMJ Evidence-Based Medicine Published Online First: 19 July 2022. doi: 10.1136/bmjebm-2022-111952. Retrieved 9 August 2022: https://ebm.bmj.com/content/early/2022/07/19/bmjebm-2022-111952
Hedges K, 2021, Correspondence with the Government of Canada, Responsible Conduct of Research, Tri-council Federal Office Panel on the responsible conduct of research, The Secretariat on Responsible Conduct of Research (SRCR) on behalf of Workplace Health Without Borders WHWB (International). Retrieved 9 August 2022: https://healthcareworkersaustralia.com/wp-content/uploads/2020/08/REBTri...
ISO 7708:1995, Air quality — Particle size fraction definitions for health-related sampling. Retrieved 9 August 2022: https://www.iso.org/standard/14534.html
Justice Philippe Bouvier (Quebec court decision) (2021):
(Paragraph 16 of Décision 735965 (N95) of the TRIBUNAL ADMINISTRATIF DU TRAVAIL
(Division de la santé et de la sécurité du travail) of March 23, 2021).([16] Par ailleurs, le Tribunal
retient que l’un des modes de transmission du virus duSRAS-CoV-2 est la voie aérienne ou par
inhalation. Dans cette perspective, les masquesmédicaux, qu’ils soient qualifiés de chirurgical ou
de procédure, ne représentent pas une protection efficace pour les travailleurs affectés aux
zones chaudes et tièdes. Le Tribunaljuge également que les Employeurs ne se sont pas acquittés
de leurs obligations en matière de santé et sécurité du travail dans la détermination des zones à
risque et de la création des équipes dédiées).
McMaster University (Canada), Office of Academic Integrity 2021, follow up correspondence to Hedges K, 2021. Retrieved 9 August 2022: https://www.aerosoltransmissioncoalition.ca/_files/ugd/cdecb4_f3401b5e36...
National Institute for Health and Care Research (Funding and Awards), “WIPPET: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 in healthcare workers”. Retrieved 9 August 2022: https://fundingawards.nihr.ac.uk/award/NIHR135521
Njoo H 2021, Deputy Chief Public Health Officer, Interim Vice-President, Infectious Disease Prevention and Control Branch, Public Health Agency of Canada (PHAC), March 2021, response to correspondence (CATC of January 4, 2021). Retrieved 9 August 2022: https://www.aerosoltransmissioncoalition.ca/_files/ugd/cdecb4_08749cfd02...
Oksanen, LM, Sanmark, E, Oksanen, E, SA, Antilla, VJ, Paterno, JJ, Lappalainen, M, Lehtonen, L, Geneid, A 2021, “Sources of healthcare workers’ COVID-19 infections and related safety guidelines”. International Journal of Occupational Medicine and Environmental Health (IJOMEH 2021; 34 (2)). Retrieved 9 August 2022: http://ijomeh.eu/Sources-of-healthcare-workers-COVID-19-infections-and-r...
Tang JW, Bahnfleth WP, Bluyssen PM, et al. (2021), Dismantling myths on the airborne transmission of severe acute respiratory syndrome coronavirus (SARS-CoV-2). J Hosp Infect. 2021;110:89–96. Retrieved 9 August 2022: https://www.journalofhospitalinfection.com/article/S0195-6701(21)00007-4/fulltext
Workplace Health Without Borders (WHWB) International, April 2020, correspondence with the Government of Canada, Minister of Health and Chief Public Health Officer Public Health Agency of Canada. Retrieved 9 August 2022: https://www.ioha.net/wp-content/uploads/2020/04/WHWB-to-Canada-Minister-...
World Health Organization WHO (2021)Coronavirus disease (COVID-19): How is it transmitted? [news release]. Geneva: World Health Organization; modified 2021 Apr. 30. Available: https://www.who.int/news-room/q-a-detail/coronavirus-disease-covid-19-ho...
US National Library of Medicine ClinicalTrials.gov, Medical Masks vs N95 Respirators for COVID-19 - ClinicalTrials.gov Identifier: NCT04296643, Retrieved 9 August 2022: https://clinicaltrials.gov/ct2/show/NCT04296643 see also: https://www.smartpatients.com/trials/NCT04296643
In their article McPherson and Speed claim that NICE’s independence seems to have diminished over time, and that it has been significantly undermined during the COVID-19 pandemic. They attempt to explain how various soft political factors may operate and how they undermine NICE’s scientific integrity.
The authors begin by suggesting that NICE’s re-establishment as a non-departmental public body (NDPB) in 2013 was prompted by the need to “increase the deniability of rationing claims or for other political purposes”.
Rather surprisingly, the authors then go on to claim that:
“This revision to the relationship can be regarded as a move towards a more explicit form of meta-governance, whereby government mechanisms are enacted through a range of quasi-autonomous bureaucratic devices.”
and further that:
“decisions about access to healthcare, for example, can be made remotely from ministers and political motive obscured by claims of the need for availability to be determined by science, not politics."
These statements are baffling because the legal position is clear. As a statutory corporation NICE is more, rather than less, independent as an arms length body (ALB) and as a body subject to administrative law and the administrative court, NICE is positively required as a matter of law to reach its decisions independently. If it did not do so its decision would be subject to being overturned by the courts. Furthermore, the regulations...
In their article McPherson and Speed claim that NICE’s independence seems to have diminished over time, and that it has been significantly undermined during the COVID-19 pandemic. They attempt to explain how various soft political factors may operate and how they undermine NICE’s scientific integrity.
The authors begin by suggesting that NICE’s re-establishment as a non-departmental public body (NDPB) in 2013 was prompted by the need to “increase the deniability of rationing claims or for other political purposes”.
Rather surprisingly, the authors then go on to claim that:
“This revision to the relationship can be regarded as a move towards a more explicit form of meta-governance, whereby government mechanisms are enacted through a range of quasi-autonomous bureaucratic devices.”
and further that:
“decisions about access to healthcare, for example, can be made remotely from ministers and political motive obscured by claims of the need for availability to be determined by science, not politics."
These statements are baffling because the legal position is clear. As a statutory corporation NICE is more, rather than less, independent as an arms length body (ALB) and as a body subject to administrative law and the administrative court, NICE is positively required as a matter of law to reach its decisions independently. If it did not do so its decision would be subject to being overturned by the courts. Furthermore, the regulations governing NICE specifically prevent the Secretary of State from directing NICE as to the content of its recommendations and any such purported direction would be a legal nullity. NICE’s reestablishment as an NDPB rather than a special health authority increased its independence because now any change to its powers or governance can only be made by Parliament, whereas as a special health authority such changes could be made by ministers alone.
We would like to comment on the two main key messages of the article.
The first is the assertion that the NICE processes for developing rapid guidelines for COVID-19 reveals that “the explicit removal of some or all scientific checks and balances in an emergency situation suggests that the central reliance of NICE on claims to scientific legitimacy is not in fact central at all. Rather, it is the first feature to be removed in the interests of expediency as though scientific processes were unnecessary bureaucracy.”
The authors suggest that political drivers could now, without any new legal agreement, prior discussion in parliament or amendment to the Framework Agreement, directly influence the scope and content of rapid guidelines. This suggestion makes very little sense since, other than topic selection there is no way in which a “political” driver could impact on any of NICE’s work.
In relation to the rapid guidelines, we remained independent from government. The guidelines were developed at the request of NHS England and NHS Improvement in response to the COVID-19 pandemic, a level 4 national emergency. Normally a topic selection oversight group at NICE considers topics for guideline development, taking into account a range of factors such as:
1. Whether there is existing NICE-accredited guidance on which to base a quality standard that encompasses the whole of the topic
2. The priority given to the topic by commissioners and professional organisations, and organisations for people using services, their families and carers
3. The health and care burden, and the potential to improve outcomes and quality of life
NICE then discusses topics identified in this way with NHS England, the Department of Health and Social Care, and Public Health England, and a prioritised list is agreed by these 3 bodies.
On 17 March 2021, we moved our priorities for the first wave of the pandemic to publish only those guidelines that were therapeutically critical and/or addressed COVID-19 diagnostic or therapeutic interventions. We worked with NHS England and NHS Improvement to identify topics to support managing symptoms of COVID-19, managing conditions that increased risk, or providing services during the pandemic. We developed interim process and methods that retained the core elements of scoping, evidence search and retrieval, working with experts, consultation, equality impact assessment and quality assurance. Inevitably, because of the urgency with which the guidance was required by the system, the process was rapid.
It is not an erosion of scientific or political independence to take into account a range of different views, including those of NHS England, especially in a national emergency. If we had used our normal process and methods for example by including a 4-week consultation period, we would have missed the optimum time identified by clinicians and commissioners for the guidance to be most useful to those managing pandemic. We achieved an optimal balance of speed and engagement for consultation, with a significant volume of comments received from a wide range of organisations.
Because COVID-19 is a new disease, evidence and practice are developing rapidly and we have implemented a process to keep the guidelines up to date as new evidence emerges. The guidelines have been very well received by clinicians and commissioners and our rapid response widely praised.
The second key message of the article is that “NICE cannot be truly led by science, in part because of its relationship to the state, however obscure that relationship has been made.”
NICE is not, and never has been, a ‘scientific authority’. Indeed, and as the authors acknowledge, in 2005, NICE published a guide setting out the social and scientific value judgements that informed our approach to developing guidance. The Social Value Judgements document helped our advisory committees resolve uncertainty in the available evidence. It informed their judgements when developing guidance, by giving them a set of principles. The Social Value Judgements were originally designed to support decision-making in guidance on new technologies. NICE’s remit has grown significantly since then. We now produce a wide range of guidance for different audiences, including local government and social care providers, which draws on a wider range of evidence. The original Social Value Judgements document remains relevant to our work, and much of what it contains is included in our methods and process manuals. In 2019 we replaced our Social Value Judgement document with a statement of our principles. This focuses on the key principles that are universal to all our guidance and standards and explains the morals, ethics and values that underpin our recommendations.
We were always clear that we would create recommendations for the system based on the evidence, but also taking into account a range of different morals, ethics and values from patients, clinicians, commissioners and other users of our guidance. Our independent advisory groups are expected to use our principles, along with our methods and process guides and the NICE charter, to inform their decisions.
One of the principles is the use of independent advisory committees to develop recommendations. This is to ensure that our recommendations are unbiased and objective and relevant for the wide range of people affected by our guidance.
We have a rigorous approach to managing conflicts of interest, with a policy that is world-leading in its standards. Committees include people from the NHS, commissioners and providers of social care, local authorities, academia, relevant industries, organisations that represent people who use services and carers, and the general public.
We also require committees to take into account stakeholder comments submitted during open consultation, and I would argue that this is a more robust, reliable and transparent method of ensuring quality and relevance than any process of traditional peer review – in fact quite the opposite of ‘light touch’. We publish both the comments we review and the responses to those comments.
In summary, NICE is an independent body that balances science, expertise and social and moral values to produce guidance informed by the best available evidence. We had to adapt and respond to an unprecedented set of circumstances in developing and maintaining guidance on COVID-19. Perhaps the authors might more usefully have addressed the question as to what else we should have done in response to a pandemic? We would argue that retaining our existing processes and topics without regard to the urgency of the situation would have been a manifestly worse position.
Rapid Response, BMJ Evidence-Based Medicine
Re: Popp M, Kranke P, Meybohm P, et al. Evidence on the efficacy of ivermectin for covid-19: another story of apples and oranges. BMJ Evidence-Based Medicine Published Online First: 20 August 2021. doi: 10.1136/bmjebm-2021-111791
Ivermectin in Covid-19
Andrew Bryant MSc
Population Health Sciences Institute, Newcastle University
Baddiley-Clark Building, Richardson Road, Newcastle upon Tyne NE2 4AX, UK
Email: andy.bryant@ncl.ac.uk
Theresa A Lawrie MBBCh PhD
Edmund J Fordham PhD FInstP
EbMCsquared, a Community Interest Company
Northgate House, Upper Borough Walls, Bath BA1 1RG, UK
Scott Mitchell MBChB MRCS
Emergency Department, Princess Elizabeth Hospital, Guernsey
To the Editor
The sole substantive critique in this Letter[1] is the description of Bryant[2] et al. (hereafter “Bryant”) as a “bowl of colourful fruit salad”[1], because of the pre-specified comparison of “ivermectin” vs “no ivermectin”. Trials with (potentially) active comparators were indeed included. Reflection should show that any bias is conservatively against ivermectin. Helpful control interventions would dilute the apparent benefit of ivermectin, relative to inactive comparators exclusively. Efficacy will be understated, not overstated, with respect to controls.
Unsuspected active agents in ivermectin combination therapies might...
Rapid Response, BMJ Evidence-Based Medicine
Re: Popp M, Kranke P, Meybohm P, et al. Evidence on the efficacy of ivermectin for covid-19: another story of apples and oranges. BMJ Evidence-Based Medicine Published Online First: 20 August 2021. doi: 10.1136/bmjebm-2021-111791
Ivermectin in Covid-19
Andrew Bryant MSc
Population Health Sciences Institute, Newcastle University
Baddiley-Clark Building, Richardson Road, Newcastle upon Tyne NE2 4AX, UK
Email: andy.bryant@ncl.ac.uk
Theresa A Lawrie MBBCh PhD
Edmund J Fordham PhD FInstP
EbMCsquared, a Community Interest Company
Northgate House, Upper Borough Walls, Bath BA1 1RG, UK
Scott Mitchell MBChB MRCS
Emergency Department, Princess Elizabeth Hospital, Guernsey
To the Editor
The sole substantive critique in this Letter[1] is the description of Bryant[2] et al. (hereafter “Bryant”) as a “bowl of colourful fruit salad”[1], because of the pre-specified comparison of “ivermectin” vs “no ivermectin”. Trials with (potentially) active comparators were indeed included. Reflection should show that any bias is conservatively against ivermectin. Helpful control interventions would dilute the apparent benefit of ivermectin, relative to inactive comparators exclusively. Efficacy will be understated, not overstated, with respect to controls.
Unsuspected active agents in ivermectin combination therapies might contribute bias the other way, but could only bias a meta-analysis toward an illusory conclusion of ivermectin efficacy if the same adjunct were dominant among studies or patients. An effective “Adjunct X” (ivermectin presumed ineffective) and synergy between the two would not be resolved, but either way an effective therapy would have been demonstrated.
Specifically, in Bryant[2], the only candidate (cited in Popp et al.[3] – hereafter “Popp” – as grounds for exclusion) is doxycycline, which contributed just three included studies[4,5,6] coming nowhere near dominance in Bryant[2].
The principal flaw in Popp[3] is the exclusion of all prior data not conforming to their own post hoc specification, by which device most available evidence is simply disregarded. Tidy experimental design is no doubt to be welcomed, but wilful disregard of available but untidy evidence, merely because some thought may be required in interpretation, is intellectual laziness.
The insinuation[1] that Bryant did not perform “careful grading of the certainty of evidence” is baseless. The review team included three highly experienced systematic reviewers two of whom are guideline methodologists. GRADE criteria[7], and WHO guidance[8], were used to rate evidence certainty.
The further claims[1] that Bryant[2] “misuse[s] established evidence assessment tools as a guise for quality of evidence synthesis”[1] and tried “to create pseudo-trustworthiness” are unsupported by any evidence. Misleading information certainly abounds in social media[1] as well as journal opinion pieces[9,10]. However, Bryant[2] is a non-commissioned research paper that followed PRISMA[11] systematic review guidelines and has no motives other than disinterested humanitarian ones. In a learned journal, unsupported assertions of insincere motives should answer themselves.
However, Bryant[2] is a non-commissioned research paper that followed PRISMA[11] systematic review guidelines and has no motives other than disinterested humanitarian ones, following other reviews of the large body of evidence of ivermectin’s utility in Covid-19[12]. In a learned journal, unsupported assertions of insincere motives are best left to answer themselves.
Funding: None.
Conflicts of interest: AB TAL EJF and SM are co-authors of Ref [2] attacked in the Letter [1]. They were members of the British Ivermectin Recommendation Development (BiRD) panel at the “Evidence to Decision” event convened on 20 February 2021. TAL and AB were members of the steering group and did not vote. EJF and SM were ordinary members of the panel. BiRD is a public information activity managed by EbMCsquared, a non-profit Community Interest Company funded by public donations. EJF and SM are unpaid volunteers entirely without financial interest. EJF is a member of the Health Advisory and Recovery Team (HART), an unincorporated membership association with no financial or material interests in ivermectin or any other medical product. This work, and Ref [2], are not projects of HART, and are not funded or influenced in any way by them
References
[1] Popp M, Kranke P, Meybohm P, et al. Evidence on the efficacy of ivermectin for covid-19: another story of apples and oranges. BMJ Evidence-Based Medicine Published Online First: 20 August 2021. doi: 10.1136/bmjebm-2021-111791
[2] Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of covid-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Therap 2021; 28, e434–460. doi:10.1097/MJT.0000000000001402
[3] Popp M, Stegemann M, Metzendorf M-I, et al. Ivermectin for preventing and treating covid-19. Cochrane Database Syst Rev 2021;7:CD015017. doi: 10.1002/14651858.CD015017.pub2
pmid: http://www.ncbi.nlm.nih.gov/pubmed/34318930
[4] Hashim, H. A., Maulood, M. F., Rasheed, A. M., Fatak, D. F., Kabah, K. K. & Abdulamir, A. S. (2020). Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv preprint doi: 10.1101/2020.10.26.20219345
[5] Mahmud, R., Rahman, M. M., Alam, I., Ahmed, K. G. U., Kabir, A. H., Sayeed, S. J. B., et al. (2021). Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. Journal of International Medical Research, 49, 030006052110135. doi: 10.1177/03000605211013550
[6] Chowdhury, A. T. M. M., Shahbaz, M., Karim, M. R., Islam, J., Guo, D. & He, S. (2020). A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients. Research Square preprint, doi: 10.21203/rs.3.rs-38896/v1
[7] GRADE Working Group 2020). GRADE 2020: Grading of Recommendations Assessment, Development and Evaluation (GRADE) https://www.gradeworkinggroup.org
[8] World Health Organization (2014). WHO handbook for guideline development. https://apps.who.int/iris/handle/10665/145714
[9] Parrish, A. G., Blockman, M., Cohen, K., Dawood, H., de Waal, R., Gray, A. L., Kredo, T., Leong, T. D., Nel, J., Rees, H. & Reubenson, G. (2021). Meta-analytic magic, ivermectin, and socially responsible reporting. South Africa Medical Journal, http://www.samj.org.za/index.php/samj/article/view/13373
[10] Garegnani, L. I., Madrid, E. & Meza, N. (2021). Misleading clinical evidence and systematic reviews on ivermectin for COVID-19. BMJ Evidence-Based Medicine, doi: 10.1136/bmjebm-2021-111678
[11] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372. doi: 10.1136/bmj.n71. Accessed 22 July 2021.
[12] Kory, P., Meduri, G. U., Varon, J., Iglesias, J. & Marik, P. E. (2021). Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. American Journal of Therapeutics, 28, e299-e318. doi: 10.1097/MJT.0000000000001377
Thank you for your Letter and concerns raised about delays to registration and failure to identify similar systematic review protocols in PROSPERO. PROSPERO, which provides registration free of charge, now receives over 47,000 submissions annually including both new submissions and resubmissions (from authors whose original submission required revision owing to low quality or incomplete information). With only 1.7 FTE administrative staff funded to manage PROSPERO, demand for registration outstrips capacity of staff to process requests.
Previous appeals to PROSPERO users to improve the quality of submission and thus reduce the need for query, feedback and resubmission and consequently demand on the register were unsuccessful. With the intention of reducing further delays, in 2020, a decision was made to automatically publish records waiting for more than 30 days from submission, providing they pass a series of automatic checks (assessing whether a record is submitted in English language and includes information about review methodology). This allowed us to focus efforts on supporting the research endeavour surrounding the global COVID-19 pandemic. We aim to publish reviews related to covid by the end of the next working day. As this has reduced the time to registration and been met with approval by the review community, we have decided to continue automatic publishing system. Future development plans involve exploring how a more detailed automatic checking process...
Thank you for your Letter and concerns raised about delays to registration and failure to identify similar systematic review protocols in PROSPERO. PROSPERO, which provides registration free of charge, now receives over 47,000 submissions annually including both new submissions and resubmissions (from authors whose original submission required revision owing to low quality or incomplete information). With only 1.7 FTE administrative staff funded to manage PROSPERO, demand for registration outstrips capacity of staff to process requests.
Previous appeals to PROSPERO users to improve the quality of submission and thus reduce the need for query, feedback and resubmission and consequently demand on the register were unsuccessful. With the intention of reducing further delays, in 2020, a decision was made to automatically publish records waiting for more than 30 days from submission, providing they pass a series of automatic checks (assessing whether a record is submitted in English language and includes information about review methodology). This allowed us to focus efforts on supporting the research endeavour surrounding the global COVID-19 pandemic. We aim to publish reviews related to covid by the end of the next working day. As this has reduced the time to registration and been met with approval by the review community, we have decided to continue automatic publishing system. Future development plans involve exploring how a more detailed automatic checking process can be implemented. Furthermore , we intend to reduce the time from receipt to automatic publication from 30 days to 10 days.
To maximise effective searching and prevent similar records being missed, PROSPERO is also exploring automatic identification of similar reviews pre-submission and a requirement for authors to explain how their proposed review is different and/or needed. This may help to reduce duplication and consequently, research waste. We hope these developments will also improve user experience and the quality of our service.
Yours sincerely,
Ruth Walker and Connor Evans on behalf of the PROSPERO team.
Pawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.
First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we in...
Pawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.
First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we included in our paper a review of the literature demonstrating that elderly people with the highest levels of LDL-C show either an equal or lower rate of mortality than people with the lowest LDL-C6. Other work, as well, has shown that FH people at 70 years of age have a significantly lower 10 year mortality rate compared to the general population7. Therefore, we find no reason to recommend that FH people reduce their LDL-C levels with diet or medication.
The primary purpose of our paper was to point out that low cholesterol, low saturated fat diets have been recommended to FH individuals for over 80 years, without any evidence of benefit. Indeed, we stated in our paper that diets that are low in fat are therefore high in carbohydrates, which may promote an atherogenic biomarker profile. What we did recommend was that FH individuals with components of the metabolic syndrome, e.g., excess weight, hypertension, hyperinsulinemia or hyperglycemia, would benefit from a diet low in carbohydrates. Support for this recommendation is based in the vast literature on clinical trials utilizing the low carbohydrate diet (LCD), which has shown its effectiveness in improving CHD-sensitive biomarkers, at a level equal to or superior to low fat diets8. The well-established benefits of an LCD in improving CHD-sensitive biomarkers supported our recommendation that a clinical trial should be performed with LCD only in FH individuals with components of the metabolic syndrome or excess hypercoagulation markers.
Second, based on the findings of 3 publications, two of them conducted on non-FH rodents and one in non-FH people, Pawlak claimed that our recommendation of the LCD for FH would “exacerbate atherosclerosis”. It is therefore important to assess whether the findings of these three papers justify his concern that the LCD is inherently atherogenic.
Two studies Pawlak cited were conducted on genetically manipulated mice designed to model human atherosclerosis9 10. Research on a rodent model of a human disease should be scrutinized closely to satisfy criteria in which the methods and biomarker outcomes are comparable to the human condition. These two studies do not satisfy these criteria. The diets of the animals are unlike a typical diet a human would consume, in general, and certainly do not match the diet of someone on an LCD. In the Foo et al.,9 study, the food was composed of sugar (8.4%), corn starch (3.6%), casein protein (45%) and milkfat (43%). This diet has no relevance to human nutrition, with one of numerous flaws being that an LCD is typically composed of 20-25% protein, 60-70% fat and 10-15% carbohydrates. Indeed, a diet that contains more protein than fat is likely to make a person ill. The second study by Kostogrys et al.,10 as well, contained a diet for the rodents with a dietary composition that no human should consume; it contained 52% protein, 12% sugar, 5% corn starch, 21% fat (butter), and the remainder as cellulose and minerals. Confirmation that these findings are unrelated to human research on LCD is that in both studies the mice developed hypertriglyceridemia, an effect that does not happen in people on LCD8. These rodent studies, therefore, have no translational value toward understanding LCD effects on CHD.
Animal research that is more relevant to mechanisms underlying premature CHD in FH individuals is provided by the Watanabe rabbit model of FH, which has high cholesterol, elevated coagulation factors (Factor VIII and fibrinogen) and develops human-like atherosclerosis.11 12 It is of value that the development of atherosclerosis in the Watanable rabbit was prevented by probucol, a medication which also reduces cardiovascular events in FH people.13 Most importantly, probucol reduced coagulation factor levels without lowering their high cholesterol.12
Pawlak cited a 20 year old clinical study that he asserted documented “the progression and the severity of CAD” (coronary artery disease) in people on an LCD. The problems with this cited study are so extensive they could fill a textbook on flawed scientific methods. First, the repeated blood work and cardiac imaging in this year-long intervention study would have had a very high cost, but no funding source was mentioned in the paper. Second, subjects were given dietary guidance, but the study did not include a registered dietician. Third, it is stated that each individual was questioned regarding dietary habits, but there is no record of what the subjects consumed. Specifically, there is no quantification of the categories, macronutrients or amount of food the subjects in the two groups ate. Fourth, there is a vague, unsubstantiated statement that a subset of patients adopted a ‘high-protein diet’, which, in theory, is equivalent to an LCD. However, there is no confirmation as to whether the ‘high-protein diet’ as described by Fleming was an LCD. Fifth, this author published related work with the same dietary program that demonstrated an increase in triglycerides in subjects on a high fat diet. The finding that people on the high fat diet developed hypertriglyceridemia is inconsistent with every other study on LCD effects on triglycerides. Overall, the work by Fleming is flawed at every level of analysis, and his findings have not been replicated by any LCD study.
The fact that Pawlak has depended on three fatally flawed studies to justify his claims that an LCD is harmful provides strong support for our contention that there is no high caliber research that demonstrates the LCD is harmful. A relevant year-long study conducted at Stanford University demonstrated that the LCD was equal or superior to other diets, including a low saturated fat (Ornish) diet, in terms of cardiovascular biomarker risk outcomes.14
Finally, Pawlak praised the effects of a low-fat, vegetarian diet in improving cardiovascular health, citing work by Ornish et al.15 However, the Ornish work was not solely a diet study. It involved an experimental group that was prescribed an intensive lifestyle intervention that included a low fat, vegetarian diet, as well as aerobic exercise sessions, stress management training, smoking cessation, group psychosocial support, and they were told to avoid sugar consumption. Control subjects were given no interventions other than to follow routine advice from their personal physicians. The multi-factorial nature of the intervention group does not permit the conclusion that any one factor, such as diet, was causally related to the outcomes of the study. It should be noted, as well, that despite the intensive lifestyle intervention in the experimental group, there was no difference in hard cardiovascular outcomes, such as the incidence of myocardial infarctions, coronary artery bypass grafts or death, between the two groups.
In conclusion, Pawlak has failed to justify his charge that we have committed malpractice by recommending that FH individuals with components of metabolic syndrome should follow a carbohydrate restricted diet.
1. Pawlak R. Low carbohydrate diets should NOT be recommended for patients with familiar hypercholesterolaemia. BMJ-Evidence Based Medicine 2020.
2. Diamond DM, Alabdulgader AA, de Lorgeril M, et al. Dietary Recommendations for Familial Hypercholesterolaemia: an Evidence-Free Zone. BMJ Evid Based Med 2020.
3. Ravnskov U, de Lorgeril M, Diamond DM, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Expert Rev Clin Pharmacol 2018;11(10):959-70.
4. Gaudet D, Vohl MC, Perron P, et al. Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation 1998;97(9):871-77.
5. Ravnskov U, de Lorgeril M, Kendrick M, et al. Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Med Hypotheses 2018;121:60-63.
6. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. Bmj Open 2016;6(6).
7. Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992-2010. J Am Heart Assoc 2014;3(6):e001236.
8. Diamond DM, O'Neill BJ, Volek JS. Low carbohydrate diet: are concerns with saturated fat, lipids, and cardiovascular disease risk justified? Curr Opin Endocrinol Diabetes Obes 2020;27(5):291-300.
9. Foo SY, Heller ER, Wykrzykowska J, et al. Vascular effects of a low-carbohydrate high-protein diet. Proc Natl Acad Sci U S A 2009;106(36):15418-23.
10. Kostogrys RB, Franczyk-Zarow M, Maslak E, et al. Low carbohydrate, high protein diet promotes atherosclerosis in apolipoprotein E/low-density lipoprotein receptor double knockout mice (apoE/LDLR(-/-)). Atherosclerosis 2012;223(2):327-31.
11. Watanabe Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). Atherosclerosis 1980;36(2):261-8.
12. Mori Y, Wada H, Nagano Y, et al. Hypercoagulable state in the Watanabe heritable hyperlipidemic rabbit, an animal model for the progression of atherosclerosis. Effect of probucol on coagulation. Thromb Haemost 1989;61(1):140-3.
13. Yamashita S, Hbujo H, Arai H, et al. Long-term probucol treatment prevents secondary cardiovascular events: a cohort study of patients with heterozygous familial hypercholesterolemia in Japan. J Atheroscler Thromb 2008;15(6):292-303.
14. Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women. Jama-Journal of the American Medical Association 2007;297(9):969-77.
15. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998;280(23):2001-7.
In a systematic review of cholesterol reduction clinical trials, DuBroff et al claimed that “the evidence presented challenges cardiovascular disease prevention through targeted reductions of LDL-cholesterol”. However, it should be noted that the concept authors claim to challenge has never been proved, nor properly tested (1). This raises the question of whether there is a need to disprove an unproven concept. In science, the burden is on the proof.
Nevertheless, if it was to disprove, we must recognize the limitations of the present study. Regarding testing "the target paradigm", the authors first categorized the trials as to whether they did or did not meet average LDL-cholesterol reduction recommended by AHA/ACC 2018 guidelines (2) for individuals. Then, they intended to test the association between reaching this arbitrary target (suggested by one specific guideline) with the trial being positive or negative regarding death or cardiovascular events. However, no statistical inference was performed for this main analysis and no significance level was presented for the interaction between reaching the target and having clinical benefit. Instead, in this systematic review that intended to test a hypothesis that implied interaction phenomenon, the authors "intentionally did not perform a meta-analysis" under the justification that trials “involved three different drug classes”.
Finally, as the authors noted, it was a systematic review of s...
In a systematic review of cholesterol reduction clinical trials, DuBroff et al claimed that “the evidence presented challenges cardiovascular disease prevention through targeted reductions of LDL-cholesterol”. However, it should be noted that the concept authors claim to challenge has never been proved, nor properly tested (1). This raises the question of whether there is a need to disprove an unproven concept. In science, the burden is on the proof.
Nevertheless, if it was to disprove, we must recognize the limitations of the present study. Regarding testing "the target paradigm", the authors first categorized the trials as to whether they did or did not meet average LDL-cholesterol reduction recommended by AHA/ACC 2018 guidelines (2) for individuals. Then, they intended to test the association between reaching this arbitrary target (suggested by one specific guideline) with the trial being positive or negative regarding death or cardiovascular events. However, no statistical inference was performed for this main analysis and no significance level was presented for the interaction between reaching the target and having clinical benefit. Instead, in this systematic review that intended to test a hypothesis that implied interaction phenomenon, the authors "intentionally did not perform a meta-analysis" under the justification that trials “involved three different drug classes”.
Finally, as the authors noted, it was a systematic review of studies not suited to test the paradigm of targets. The primary test for this hypothesis should be the randomization of patients to have drug doses adjusted to a target goal or to have a fixed dose.
In fact, a proper conclusion of a systematic review that aimed to “test the validity of this [target] paradigm” would be for absence of evidence, instead of claiming evidence of absence by very limited data analysis against a unproven concept.
That being said, the value of using LDL-cholesterol targets has never been demonstrated, nor should be reinforced by guidelines.
2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2019 Jun 18;139(25):e1182-e1186]. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking into account studies that not official report it as ODYSSEY long Term and ODYSSEY COMBO I.
On the other hand, this article enlists essays in secondary prevention like FOURIER or IMPROVE-IT but it doesn’t include the HPS –with its huge statistical weight- or PROSPER –which achieves minor coronary death in elderly patients- or PROVE-IT or TNT. This situation looks like a whimsical selection without a solid support instead of a consistent piece of evidence.
I believe LDL central role in atherosclerosis is not quit questionable as the methodology used to calculate cardiovascular risk on primary prevention population or the residual risk in patients with prior heart disease. In my opinion, this would allow us to take the cardiovascular disease as the first cause of death of the world.
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking into account studies that not official report it as ODYSSEY long Term and ODYSSEY COMBO I.
On the other hand, this article enlists essays in secondary prevention like FOURIER or IMPROVE-IT but it doesn’t include the HPS –with its huge statistical weight- or PROSPER –which achieves minor coronary death in elderly patients- or PROVE-IT or TNT. This situation looks like a whimsical selection without a solid support instead of a consistent piece of evidence.
I believe LDL central role in atherosclerosis is not quit questionable as the methodology used to calculate cardiovascular risk on primary prevention population or the residual risk in patients with prior heart disease. In my opinion, this would allow us to take the cardiovascular disease as the first cause of death of the world.
The clinical evidence we produce which impacts the care we deliver to patients must have the highest standards. Unlike biomedical evidence, the evidence behind our treatments, risk factors and diagnostic tests should be relevant to the patients and clinicians who practice at the coal-face and real-world of General Practice and our hospitals.
Show MoreWe may have had 250,000 'peer-reviewed' articles relating to COVID-19 (whatever credibility that affords), but allowing biomedical assumptions to creep into guidelines and direct patient care, is taking a step backwards in evidence-based practice. COVID saw a multitude of 'experts' give their opinion freely in the media and on social media platforms, based on biomedical ‘evidence’, on opinion, through the platforming of academic-status and on dubious case-studies. This was self-evidently un-scientific, and arguably has set science back. Yet this article seems to advance the notion that this evidence should impact patient care.
So much has to be done to enable EBM to flourish- yet this article will likely set EBM back. The evidence underpinning our treatments should be quantifiable in absolute terms, and the uncertainties and conflicts of interests (COIs) acknowledged. The evidence behind our risk factors characterised in absolute terms, within the context of confounders and biases from observational studies. Our diagnostic tests should be understood within the context of odds and post-test probability. O...
Airborne transmission and inhalation, of SARS-CoV-2 is recognized by international public health agencies (Addleman et al. 2021) from both short- and long-range aerosol transmission (Tang et al. 2021).
Show MoreWhen comparing filtering face piece (FFP) respirators, with a surgical (medical) masks, for protection against an inhalable (ISO 7708) airborne virus such as SARS-CoV-2, “EQUIPOISE” a central tenet for conducting a randomised control trial (RCT), does not exist. The futility of using a RCT is analogous to carrying out a study in a construction site for hard hats or seat belts in a passenger vehicle. FFP respirators used in Canada are selected and used in accordance with CAN/CSA-Z94.4-18 (Selection, use, and care of respirators). Specifications are provided in CSA Z94.4.1:21 (Performance of filtering respirators).
At least two international studies using RCT have been initiated since the start of the COVID-19 pandemic.
a) United Kingdom: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 for healthcare workers (The funding committee did not recommend funding).
b) Canada, multi-centre: where nurses are randomized to either use of a medical mask or to a fit-tested N95 respirator when providing care for patients with febrile respiratory illness.
The findings from a poorly designed RCT may also be used as improper and biased rationale to downgrade respirator (masks...
In their article McPherson and Speed claim that NICE’s independence seems to have diminished over time, and that it has been significantly undermined during the COVID-19 pandemic. They attempt to explain how various soft political factors may operate and how they undermine NICE’s scientific integrity.
The authors begin by suggesting that NICE’s re-establishment as a non-departmental public body (NDPB) in 2013 was prompted by the need to “increase the deniability of rationing claims or for other political purposes”.
Rather surprisingly, the authors then go on to claim that:
“This revision to the relationship can be regarded as a move towards a more explicit form of meta-governance, whereby government mechanisms are enacted through a range of quasi-autonomous bureaucratic devices.”
and further that:
“decisions about access to healthcare, for example, can be made remotely from ministers and political motive obscured by claims of the need for availability to be determined by science, not politics."
These statements are baffling because the legal position is clear. As a statutory corporation NICE is more, rather than less, independent as an arms length body (ALB) and as a body subject to administrative law and the administrative court, NICE is positively required as a matter of law to reach its decisions independently. If it did not do so its decision would be subject to being overturned by the courts. Furthermore, the regulations...
Show MoreRapid Response, BMJ Evidence-Based Medicine
Re: Popp M, Kranke P, Meybohm P, et al. Evidence on the efficacy of ivermectin for covid-19: another story of apples and oranges. BMJ Evidence-Based Medicine Published Online First: 20 August 2021. doi: 10.1136/bmjebm-2021-111791
Ivermectin in Covid-19
Andrew Bryant MSc
Population Health Sciences Institute, Newcastle University
Baddiley-Clark Building, Richardson Road, Newcastle upon Tyne NE2 4AX, UK
Email: andy.bryant@ncl.ac.uk
Theresa A Lawrie MBBCh PhD
Edmund J Fordham PhD FInstP
EbMCsquared, a Community Interest Company
Northgate House, Upper Borough Walls, Bath BA1 1RG, UK
Scott Mitchell MBChB MRCS
Emergency Department, Princess Elizabeth Hospital, Guernsey
To the Editor
Show MoreThe sole substantive critique in this Letter[1] is the description of Bryant[2] et al. (hereafter “Bryant”) as a “bowl of colourful fruit salad”[1], because of the pre-specified comparison of “ivermectin” vs “no ivermectin”. Trials with (potentially) active comparators were indeed included. Reflection should show that any bias is conservatively against ivermectin. Helpful control interventions would dilute the apparent benefit of ivermectin, relative to inactive comparators exclusively. Efficacy will be understated, not overstated, with respect to controls.
Unsuspected active agents in ivermectin combination therapies might...
Thank you for your Letter and concerns raised about delays to registration and failure to identify similar systematic review protocols in PROSPERO. PROSPERO, which provides registration free of charge, now receives over 47,000 submissions annually including both new submissions and resubmissions (from authors whose original submission required revision owing to low quality or incomplete information). With only 1.7 FTE administrative staff funded to manage PROSPERO, demand for registration outstrips capacity of staff to process requests.
Previous appeals to PROSPERO users to improve the quality of submission and thus reduce the need for query, feedback and resubmission and consequently demand on the register were unsuccessful. With the intention of reducing further delays, in 2020, a decision was made to automatically publish records waiting for more than 30 days from submission, providing they pass a series of automatic checks (assessing whether a record is submitted in English language and includes information about review methodology). This allowed us to focus efforts on supporting the research endeavour surrounding the global COVID-19 pandemic. We aim to publish reviews related to covid by the end of the next working day. As this has reduced the time to registration and been met with approval by the review community, we have decided to continue automatic publishing system. Future development plans involve exploring how a more detailed automatic checking process...
Show MorePawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.
First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we in...
Show MoreTest
In a systematic review of cholesterol reduction clinical trials, DuBroff et al claimed that “the evidence presented challenges cardiovascular disease prevention through targeted reductions of LDL-cholesterol”. However, it should be noted that the concept authors claim to challenge has never been proved, nor properly tested (1). This raises the question of whether there is a need to disprove an unproven concept. In science, the burden is on the proof.
Nevertheless, if it was to disprove, we must recognize the limitations of the present study. Regarding testing "the target paradigm", the authors first categorized the trials as to whether they did or did not meet average LDL-cholesterol reduction recommended by AHA/ACC 2018 guidelines (2) for individuals. Then, they intended to test the association between reaching this arbitrary target (suggested by one specific guideline) with the trial being positive or negative regarding death or cardiovascular events. However, no statistical inference was performed for this main analysis and no significance level was presented for the interaction between reaching the target and having clinical benefit. Instead, in this systematic review that intended to test a hypothesis that implied interaction phenomenon, the authors "intentionally did not perform a meta-analysis" under the justification that trials “involved three different drug classes”.
Finally, as the authors noted, it was a systematic review of s...
Show MoreIn this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
Show MoreIn order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
Show MoreIn order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
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