Prophylaxis against covid-19: living systematic review and network meta-analysis
Bartoszko, Jessica J; Siemieniuk, Reed A C; Kum, Elena; Qasim, Anila; Zeraatkar, Dena; Ge, Long; Han, Mi Ah; Sadeghirad, Behnam; Agarwal, Arnav; Agoritsas, Thomas; Chu, Derek K; Couban, Rachel; Darzi, Andrea J; Devji, Tahira; Ghadimi, Maryam; Honarmand, Kimia; Izcovich, Ariel; Khamis, Assem; Lamontagne, Francois; Loeb, Mark; Marcucci, Maura; McLeod, Shelley L; Motaghi, Sharhzad; Murthy, Srinivas; Mustafa, Reem A; Neary, John D; Pardo-Hernandez, Hector; Rada, Gabriel; Rochwerg, Bram; Switzer, Charlotte; Tendal, Britta; Thabane, Lehana; Vandvik, Per O; Vernooij, Robin W M; Viteri-García, Andrés; Wang, Ying; Yao, Liang; Ye, Zhikang; Guyatt, Gordon H; Brignardello-Petersen, Romina
(2021) BMJ (Clinical research ed.), volume 373, pp. 1 - 12
(Article)
Abstract
OBJECTIVE: To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19. DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021.
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STUDY SELECTION: Randomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. METHODS: Random effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. RESULTS: The first iteration of this living network meta-analysis includes nine randomised trials-six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain. CONCLUSIONS: Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a supplement. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.
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Keywords: Anti-Infective Agents/pharmacology, COVID-19/prevention & control, Carrageenan/pharmacology, Chemoprevention/methods, Global Health/statistics & numerical data, Humans, Hydroxychloroquine/pharmacology, Ivermectin/pharmacology, SARS-CoV-2, Treatment Outcome, Uncertainty, General Medicine, Research Support, Non-U.S. Gov't, Meta-Analysis, Journal Article
ISSN: 1756-1833
Publisher: BMJ Publishing Group
Note: Funding Information: disclosure form at www.icmje.org/coi_disclosure.pdf and declare: BS reports receiving funding from PIPRA AG (www.pipra.ch) to conduct a systematic review and individual patient data meta-analysis on predictors of postoperative delirium in elderly people in 2020-21; funding from Mitacs Canada, Accelerate internship in partnership with Nestlé Canada to support his graduate student stipend from 2016 to 2018. Mitacs is a national, not-for-profit organisation that has designed and delivered research and training programmes in Canada, working with universities, companies, and both federal and provincial governments; and funding from the International Life Sciences Institute (ILSI)-North America to support his graduate work for his 2015 academic year. In 2016-17, BS worked part-time for the Cornerstone Research Group (CRG), a contract research organisation. The ILSI funding and being employed by CRG are outside the required three year period requested on the ICJME form. ML reports personal fees and non-financial support from Sanofi, grants and personal fees from Seqirus, and personal fees from Pfizer and Medicago outside the submitted work; and is co-investigator on an Anti-Coronavirus Therapies (ACT) randomised trial of covid-19 treatment. LG reports grants from the Ministry of Science and Technology of China, outside the submitted work. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work. Ethical approval: Not required. Funding Information: Contributors: RACS, JJB, LG, AQ, EK, and DZ contributed equally to the systematic review and are joint first authors. RACS, JJB, DZ, LG, EK, AQ, and RB-P were the core team leading the systematic review. JJB, RC, RWMV, SM, YW, ZY, CS, LY, MG, and AV-G identified and selected the studies. DZ, EK, RWMV, AA, YW, KH, HP-H, MAH, SLM, AQ, and LY collected the data. AQ, LG, AK, BS, GHG, and LT analysed the data. RB-P, HPH, AI, RAM, TD, and DC assessed the certainty of the evidence. SLM, FL, BR, TA, POV, GHG, MM, JDN, ML, BT, and GR provided advice at different stages. JJB, RACS, RB-P, and GHG drafted the manuscript. All authors approved the final version of the manuscript. RACS is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Funding: This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321; grant MM1-174897). Funding Information: 1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada 2Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, Gansu, China 3Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, Republic of Korea 4Department of Anesthesia, McMaster University, Hamilton, ON, Canada 5Department of Medicine, University of Toronto, Toronto, ON, Canada 6Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland 7Department of Medicine, McMaster University, Hamilton, ON, Canada 8Department of Medicine, Western University, London, ON, Canada 9Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina 10Wolfson Palliative Care Research Centre, Hull York Medical School, York, UK 11Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, QC, Canada 12Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada 13Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada 14Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada 15Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA 16Iberoamerican Cochrane Centre, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain 17CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain 18Epistemonikos Foundation, Santiago, Chile 19C Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile 20School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia 21Institute of Health and Society, University of Oslo, Oslo, Norway 22Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands 23Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands 24Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador DKC is an emerging clinician-scientist research fellow, supported by the Canadian Allergy, Asthma and Immunology Foundation, the Canadian Society of Allergy and Clinical Immunology, and AllerGen NCE (the Allergy, Genes and Environment Network, funded through the Canadian Institutes of Health Research). 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