Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 AMeta-analysis
Por:
Shankar-Hari, M, Vale, CL, Godolphin, PJ, Fisher, D, Higgins, JPT, Spiga, F, Savovic, J, Tierney, J, Baron, G, Benbenishty, JS, Berry, LR, Broman, N, Cavalcanti, AB, Colman, R, De Buyser, SL, Derde, LPG, Domingo, P, Omar, SF, Fernandez-Cruz, A, Feuth, T, Garcia, F, Garcia-Vicuna, R, Gonzalez-Alvaro, I, Gordon, AC, Haynes, R, Hermine, O, Horby, PW, Horick, NK, Kumar, K, Lambrecht, BN, Landray, MJ, Leal, L, Lederer, DJ, Lorenzi, E, Mariette, X, Merchante, N, Misnan, NA, Mohan, SV, Nivens, MC, Oksi, J, Perez-Molina, JA, Pizov, R, Porcher, R, Postma, S, Rajasuriar, R, Ramanan, AV, Ravaud, P, Reid, PD, Rutgers, A, Sancho-Lopez, A, Seto, TB, Sivapalasingam, S, Soin, AS, Staplin, N, Stone, JH, Strohbehn, GW, Sunden-Cullberg, J, Torre-Cisneros, J, Tsai, LW, van Hoogstraten, H, van Meerten, T, Veiga, VC, Westerweel, PE, Murthy, S, Diaz, JV, Marshall, JC, Sterne, JAC, Pomar V., Benito N., WHO Rapid Evidence Appraisal COVID
Publicada:
10 ago 2021
Resumen:
IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.
OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.
DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.
STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.
DATA EXTRACTION AND SYNTHESIS In this prospectivemeta-analysis, risk of biaswas assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I-2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.
MAIN OUTCOMES AND MEASURES The primary outcome measurewas all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.
RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P =.003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P <.001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P =.52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).
CONCLUSIONS AND RELEVANCE In this prospectivemeta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.
Filiaciones:
Shankar-Hari, M:
Guys & St Thomas NHS Fdn Trust, St Thomas Hosp, ICU Support Off, London, England
Kings Coll London, Sch Immunol & Microbial Sci, London, England
Vale, CL:
UCL, MRC Clin Trials Unit, UCL, London, England
Godolphin, PJ:
UCL, MRC Clin Trials Unit, UCL, London, England
Fisher, D:
UCL, MRC Clin Trials Unit, UCL, London, England
Higgins, JPT:
Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England
NIHR Bristol Biomed Res Ctr, Bristol, Avon, England
Univ Hosp Bristol, Natl Inst Hlth Res Appl Res Collaborat West, Bristol, Avon, England
Weston NHS Fdn Trust, Bristol, Avon, England
Spiga, F:
Univ Bristol, Bristol, Avon, England
Savovic, J:
Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England
Univ Hosp Bristol, Natl Inst Hlth Res Appl Res Collaborat West, Bristol, Avon, England
Weston NHS Fdn Trust, Bristol, Avon, England
Tierney, J:
UCL, MRC Clin Trials Unit, UCL, London, England
Baron, G:
Hop Hotel Dieu, Assistance Publ Hop Paris, Ctr Clin Epidemiol, Paris, France
Univ Paris, METHODS Team, Ctr Rech Epidemiol & Stat, INSERM UMRS 1153, Paris, France
Benbenishty, JS:
Hadassah Hebrew Univ Med Ctr, Dept Nursing, Jerusalem, Israel
Berry, LR:
Berry Consultants, Austin, TX USA
Broman, N:
Turku Univ Hosp, Dept Infect Dis, Turku, Finland
Cavalcanti, AB:
BP Beneficencia Portuguesa Sao Paulo, Rua Maestro Cardim, Sao Paulo, Brazil
Colman, R:
Univ Ghent, Dept Publ Hlth & Primary Care, Ghent, Belgium
De Buyser, SL:
Univ Ghent, Dept Publ Hlth & Primary Care, Ghent, Belgium
Derde, LPG:
Univ Med Ctr Utrecht, Dept Intens Care Med, Utrecht, Netherlands
Domingo, P:
Hosp Santa Creu & Sant Pau, Dept Infect Dis, Barcelona, Spain
Omar, SF:
Univ Malaya, Dept Med, Kuala Lumpur, Malaysia
Fernandez-Cruz, A:
Hosp Univ Puerta de Hierro Majadahonda, Internal Med Dept, Infect Dis Unit, Madrid, Spain
Feuth, T:
Turku Univ Hosp, Dept Pulm Dis, Turku, Finland
Garcia, F:
Hosp Clin Barcelona, Infect Dis Dept, IDIBAPS, Barcelona, Spain
Garcia-Vicuna, R:
Hosp Univ La Princesa IIS IP, Rheumatol, Madrid, Spain
Gonzalez-Alvaro, I:
Hosp Univ La Princesa IIS IP, Rheumatol, Madrid, Spain
Gordon, AC:
Imperial Coll London, Div Anaesthet Pain Med & Intens Care, London, England
Haynes, R:
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Univ Oxford, MRC Populat Hlth Res Unit, Oxford, England
Hermine, O:
Hop Necker Enfants Malad, Dept Hematol, Paris, France
Univ Paris, Imagine Inst, INSERM U1153, Paris, France
Horby, PW:
Univ Oxford, Ctr Trop Med & Global Hlth, Nuffield Dept Med, Oxford, England
Univ Oxford, Int Severe Acute Resp & Emerging Infect Consortiu, Oxford, England
Univ Oxford, Pandem Sci Ctr, Oxford, England
Horick, NK:
Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA
Kumar, K:
Medanta, Inst Liver Transplantat & Regenerat Med, Gurugram, India
Medanta Inst Educ & Res, Res Dept, Gurugram, India
Lambrecht, BN:
Univ Ghent, VIB Ctr Inflammat Res, Ghent, Belgium
Univ Ghent, Dept Internal Med & Pediat, Ghent, Belgium
Landray, MJ:
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Univ Oxford, MRC Populat Hlth Res Unit, Oxford, England
Leal, L:
Hosp Clin Barcelona, Infect Dis Dept, IDIBAPS, Barcelona, Spain
Lederer, DJ:
Regeneron Pharmaceut Inc, Tarrytown, NY USA
Lorenzi, E:
Berry Consultants, Austin, TX USA
Mariette, X:
Univ Paris Saclay, Ctr Immunol Viral Infect & Autoimmune Dis, INSERM UMR1184, Paris, France
Assistance Publ Hop Paris, Dept Rheumatol, Paris, France
Merchante, N:
Valme Univ Hosp, Inst Biomed Sevilla, Unit Infect Dis & Microbiol, Seville, Spain
Misnan, NA:
Minist Hlth, Hosp Sungai Buloh, Buloh, Malaysia
Mohan, SV:
Genentech Inc, San Francisco, CA 94080 USA
Nivens, MC:
Regeneron Pharmaceut Inc, Tarrytown, NY USA
Oksi, J:
Turku Univ Hosp, Dept Infect Dis, Turku, Finland
Perez-Molina, JA:
Hosp Univ Ramon y Cajal IRYCIS, Infect Dis Dept, Madrid, Spain
Pizov, R:
Hadassah Hebrew Univ Hosp, Dept Anesthesil Crit Care & Pain Med, Jerusalem, Israel
Porcher, R:
Hop Hotel Dieu, Assistance Publ Hop Paris, Ctr Clin Epidemiol, Paris, France
Univ Paris, METHODS Team, Ctr Rech Epidemiol & Stat, INSERM UMRS 1153, Paris, France
Univ Paris, INRA, INSERM, CRESS UMR1153, Paris, France
Postma, S:
Univ Hosp Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands
Rajasuriar, R:
Univ Malaya, Dept Med, Kuala Lumpur, Malaysia
Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia
Ramanan, AV:
Univ Hosp Bristol NHS Fdn Trust, Dept Paediat Rheumatol, Bristol, Avon, England
Ravaud, P:
Hop Hotel Dieu, Assistance Publ Hop Paris, Ctr Clin Epidemiol, Paris, France
Univ Paris, METHODS Team, Ctr Rech Epidemiol & Stat, INSERM UMRS 1153, Paris, France
Univ Paris, INRA, INSERM, CRESS UMR1153, Paris, France
Reid, PD:
Univ Chicago, Med Ctr, Dept Med Rheumatol, Chicago, IL 60637 USA
Rutgers, A:
Univ Hosp Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands
Sancho-Lopez, A:
Hosp Univ Puerta de Hierro Majadahonda, Dept Clin Pharmacol, Madrid, Spain
Seto, TB:
Queens Med Ctr, Ctr Outcomes Res & Evaluat, Honolulu, HI USA
Sivapalasingam, S:
Regeneron Pharmaceut Inc, Tarrytown, NY USA
Soin, AS:
Medanta, Inst Liver Transplantat & Regenerat Med, Gurugram, India
Staplin, N:
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Univ Oxford, MRC Populat Hlth Res Unit, Oxford, England
Stone, JH:
Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA
Massachusetts Gen Hosp, Dept Med Rheumatol, Boston, MA USA
Strohbehn, GW:
VA Ann Arbor, Ctr Clin Management & Res, Ann Arbor, MI USA
Sunden-Cullberg, J:
Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Infect Dis, Stockholm, Sweden
Torre-Cisneros, J:
Univ Cordoba, Reina Sofia Univ Hosp, Maimonides Inst Biomed Res Cordoba, Cordoba, Spain
Tsai, LW:
Genentech Inc, San Francisco, CA 94080 USA
van Hoogstraten, H:
Sanofi Genzyme, Global Med Affairs, Bridgewater, NJ USA
van Meerten, T:
Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands
Veiga, VC:
BP Beneficencia Portuguesa Sao Paulo, Rua Maestro Cardim, Sao Paulo, Brazil
Westerweel, PE:
Albert Schweitzer Hosp, Dept Internal Med, Dordrecht, Netherlands
Murthy, S:
Univ British Columbia, Dept Pediat, Vancouver, BC, Canada
Diaz, JV:
World Hlth Org, Clin Unit, Hlth Emergencies Programme, Geneva, Switzerland
Marshall, JC:
Univ Toronto, Li Ka Shing Knowledge Inst, St Michaels Hosp, Toronto, ON, Canada
Sterne, JAC:
Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England
NIHR Bristol Biomed Res Ctr, Bristol, Avon, England
Hlth Data Res UK South West, Bristol, Avon, England
Pomar V.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Benito N.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
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