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Drug treatments for covid-19: living systematic review and network meta-analysis.
Siemieniuk, Reed Ac; Bartoszko, Jessica J; Ge, Long; Zeraatkar, Dena; Izcovich, Ariel; Kum, Elena; Pardo-Hernandez, Hector; Qasim, Anila; Martinez, Juan Pablo Díaz; Rochwerg, Bram; Lamontagne, Francois; Han, Mi Ah; Liu, Qin; Agarwal, Arnav; Agoritsas, Thomas; Chu, Derek K; Couban, Rachel; Cusano, Ellen; Darzi, Andrea; Devji, Tahira; Fang, Bo; Fang, Carmen; Flottorp, Signe Agnes; Foroutan, Farid; Ghadimi, Maryam; Heels-Ansdell, Diane; Honarmand, Kimia; Hou, Liangying; Hou, Xiaorong; Ibrahim, Quazi; Khamis, Assem; Lam, Bonnie; Loeb, Mark; Marcucci, Maura; McLeod, Shelley L; Motaghi, Sharhzad; Murthy, Srinivas; Mustafa, Reem A; Neary, John D; Rada, Gabriel; Riaz, Irbaz Bin; Sadeghirad, Behnam; Sekercioglu, Nigar; Sheng, Lulu; Sreekanta, Ashwini; Switzer, Charlotte; Tendal, Britta; Thabane, Lehana; Tomlinson, George; Turner, Tari.
  • Siemieniuk RA; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada reed.siemieniuk@medportal.ca.
  • Bartoszko JJ; Joint first authors.
  • Ge L; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Zeraatkar D; Joint first authors.
  • Izcovich A; Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, Gansu, China.
  • Kum E; Joint first authors.
  • Pardo-Hernandez H; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Qasim A; Joint first authors.
  • Martinez JPD; Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina.
  • Rochwerg B; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Lamontagne F; Iberoamerican Cochrane Centre, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain.
  • Han MA; CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
  • Liu Q; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Agarwal A; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Agoritsas T; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Chu DK; Department of Medicine, McMaster University, Hamilton, ON, Canada.
  • Couban R; Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, Quebec, Canada.
  • Cusano E; Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, Republic of Korea.
  • Darzi A; Cochrane China Network Affiliate, Chongqing Medical University, Chongqing, China.
  • Devji T; School of Public Health and Management, Chongqing Medical University, Chongqing, China.
  • Fang B; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Fang C; Department of Medicine, University of Toronto, Toronto, ON, Canada.
  • Flottorp SA; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Foroutan F; Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland.
  • Ghadimi M; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Heels-Ansdell D; Department of Medicine, McMaster University, Hamilton, ON, Canada.
  • Honarmand K; Department of Anesthesia, McMaster University, Hamilton, ON, Canada.
  • Hou X; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Ibrahim Q; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Khamis A; Cochrane China Network Affiliate, Chongqing Medical University, Chongqing, China.
  • Lam B; School of Public Health and Management, Chongqing Medical University, Chongqing, China.
  • Loeb M; William Osler Health Network, Toronto, ON, Canada.
  • Marcucci M; Norwegian Institute of Public Health, Oslo, Norway.
  • McLeod SL; Institute of Health and Society, University of Oslo, Oslo, Norway.
  • Motaghi S; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Murthy S; Ted Rogers Center for Heart Research, Toronto General Hospital, ON, Canada.
  • Mustafa RA; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Neary JD; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Rada G; Department of Medicine, Western University, London, ON, Canada.
  • Riaz IB; Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, Gansu, China.
  • Sadeghirad B; College of Medical Informatics, Chongqing Medical University, Chongqing, China.
  • Sekercioglu N; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Sheng L; Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK.
  • Sreekanta A; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Switzer C; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Tendal B; Department of Medicine, McMaster University, Hamilton, ON, Canada.
  • Thabane L; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
  • Tomlinson G; Department of Medicine, McMaster University, Hamilton, ON, Canada.
  • Turner T; Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada.
BMJ ; 370: m2980, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-691120
Semantic information from SemMedBD (by NLM)
1. Medication Management TREATS COVID-19
Subject
Medication Management
Predicate
TREATS
Object
COVID-19
2. Therapeutic procedure TREATS COVID-19
Subject
Therapeutic procedure
Predicate
TREATS
Object
COVID-19
3. Glucocorticoids DISRUPTS Cessation of life
Subject
Glucocorticoids
Predicate
DISRUPTS
Object
Cessation of life
4. Interventional procedure compared_with Mechanical ventilation
Subject
Interventional procedure
Predicate
compared_with
Object
Mechanical ventilation
5. Pharmaceutical Preparations INHIBITS Duration
Subject
Pharmaceutical Preparations
Predicate
INHIBITS
Object
Duration
6. remdesivir compared_with lopinavir / Ritonavir
Subject
remdesivir
Predicate
compared_with
Object
lopinavir / Ritonavir
7. hydroxychloroquine compared_with remdesivir
Subject
hydroxychloroquine
Predicate
compared_with
Object
remdesivir
8. hydroxychloroquine PREDISPOSES Adverse event
Subject
hydroxychloroquine
Predicate
PREDISPOSES
Object
Adverse event
9. remdesivir PREDISPOSES Adverse event
Subject
remdesivir
Predicate
PREDISPOSES
Object
Adverse event
10. Intervention regimes AFFECTS Discontinued
Subject
Intervention regimes
Predicate
AFFECTS
Object
Discontinued
11. Mechanical ventilation TREATS COVID-19
Subject
Mechanical ventilation
Predicate
TREATS
Object
COVID-19
12. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
13. Mechanical ventilation TREATS Patients
Subject
Mechanical ventilation
Predicate
TREATS
Object
Patients
14. Medication Management TREATS COVID-19
Subject
Medication Management
Predicate
TREATS
Object
COVID-19
15. Therapeutic procedure TREATS COVID-19
Subject
Therapeutic procedure
Predicate
TREATS
Object
COVID-19
16. Glucocorticoids DISRUPTS Cessation of life
Subject
Glucocorticoids
Predicate
DISRUPTS
Object
Cessation of life
17. Interventional procedure compared_with Mechanical ventilation
Subject
Interventional procedure
Predicate
compared_with
Object
Mechanical ventilation
18. Pharmaceutical Preparations INHIBITS Duration
Subject
Pharmaceutical Preparations
Predicate
INHIBITS
Object
Duration
19. remdesivir compared_with lopinavir / Ritonavir
Subject
remdesivir
Predicate
compared_with
Object
lopinavir / Ritonavir
20. hydroxychloroquine compared_with remdesivir
Subject
hydroxychloroquine
Predicate
compared_with
Object
remdesivir
21. hydroxychloroquine PREDISPOSES Adverse event
Subject
hydroxychloroquine
Predicate
PREDISPOSES
Object
Adverse event
22. remdesivir PREDISPOSES Adverse event
Subject
remdesivir
Predicate
PREDISPOSES
Object
Adverse event
23. Intervention regimes AFFECTS Discontinued
Subject
Intervention regimes
Predicate
AFFECTS
Object
Discontinued
24. Mechanical ventilation TREATS COVID-19
Subject
Mechanical ventilation
Predicate
TREATS
Object
COVID-19
25. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
26. Mechanical ventilation TREATS Patients
Subject
Mechanical ventilation
Predicate
TREATS
Object
Patients
ABSTRACT

OBJECTIVE:

To compare the effects of treatments for coronavirus disease 2019 (covid-19).

DESIGN:

Living systematic review and network meta-analysis. DATA SOURCES WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. STUDY SELECTION Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.

METHODS:

After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.

RESULTS:

196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low.

CONCLUSION:

Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. SYSTEMATIC REVIEW REGISTRATION This review was not registered. The protocol is publicly available in the supplementary material. 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. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Respiration, Artificial / Coronavirus Infections / Betacoronavirus Type of study: Controlled clinical trial / Diagnostic study / Clinical Practice Guide / Prognostic study / Randomized controlled trials / Reviews / Systematic review Country/Region as subject: North America / Asia Language: English Journal: BMJ Journal subject: Medicine Year: 2020 Document Type: Article Affiliation country: Bmj.m2980

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Respiration, Artificial / Coronavirus Infections / Betacoronavirus Type of study: Controlled clinical trial / Diagnostic study / Clinical Practice Guide / Prognostic study / Randomized controlled trials / Reviews / Systematic review Country/Region as subject: North America / Asia Language: English Journal: BMJ Journal subject: Medicine Year: 2020 Document Type: Article Affiliation country: Bmj.m2980