Rapid Response, BMJ Evidence-Based Medicine

Andrew Bryant, Research Associate (Biostatistician), Newcastle University

Other Contributors:

Edmund J Fordham
Scott Mitchell
September 30, 2021

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

Conflict of Interest

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