Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data
Matthieu Mahévas, Viet-Thi Tran, Mathilde Roumier, Amélie Chabrol, Romain Paule, Constance Guillaud, Elena Fois, Raphael Lepeule, Tali-Anne Szwebel, François-Xavier Lescure, Frédéric Schlemmer, Marie Matignon, Mehdi Khellaf, Etienne Crickx, Benjamin Terrier, Caroline Morbieu, Paul Legendre, Julien Dang, Yoland Schoindre, Jean-Michel Pawlotsky, Marc Michel, Elodie Perrodeau, Nicolas Carlier, Nicolas Roche, Victoire De Lastours, Clément Ourghanlian, Solen Kerneis, Philippe Ménager, Luc Mouthon, Etienne Audureau, Philippe Ravaud, Bertrand Godeau, Sébastien Gallien, Nathalie Costedoat-Chalumeau
BMJ, doi:10.1136/bmj.m1844
OBJECTIVE To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen.
DESIGN Comparative observational study using data collected from routine care.
SETTING Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020. PARTICIPANTS 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care.
CONCLUSIONS Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.
RESEARCH No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe
References
Austin, Stuart, Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies, Stat Med,
doi:10.1002/sim.6607
Cao, Wang, Wen, A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19, N Engl J Med,
doi:10.1056/NEJMoa2001282
Chen, Hu, Zhang, Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial, Epidemiology,
doi:10.1101/2020.03.22.20040758
Costedoat-Chalumeau, Dunogué, Morel, Guern, Guettrot-Imbert, Hydroxychloroquine: a multifaceted treatment in lupus, Presse Med,
doi:10.1016/j.lpm.2014.03.007
Freund, Lemachatti, Krastinova, of Emergency Medicine Collaborators Group. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department, Am J Epidemiol,
doi:10.1001/jama.2016.20329.on16
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105949
Giudicessi, Noseworthy, Friedman, Ackerman, Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19), Mayo Clin,
doi:10.1016/j.mayocp.2020.03.024
Hernán, Robins, Using big data to emulate a target trial when a randomized trial is not available, Am J Epidemiol,
doi:10.1093/aje/kwv254
Kim, Sparks, Liew, Rheumatology Alliance †. A rush to judgment? Rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for covid-19, Ann Intern Med,
doi:10.7326/M20-1223
Kuznik, Bencina, Svajger, Jeras, Rozman et al., Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines, J Immunol,
doi:10.4049/jimmunol.1000702
Lenzer, Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence, BMJ,
doi:10.1136/bmj.m1335
Lescure, Bouadma, Nguyen, Clinical and virological data of the first cases of COVID-19 in Europe: a case series, Lancet Infect Dis,
doi:10.1016/S1473-3099(20)30200-0
Lunceford, Davidian, Stratification and weighting via the propensity score in estimation of causal treatment effects: a comparative study [correction in, Stat Med
Molina, Delaugerre, Goff, No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe covid-19 infection, Med Mal Infect,
doi:10.1016/j.medmal.2020.03.006
Patel, Verma, Covid-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence?, JAMA,
doi:10.1001/jama.2020.4812
Ranieri, Rubenfeld, Thompson, ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition, JAMA,
doi:10.1001/jama.2012.5669
Singer, Deutschman, Seymour, The third international consensus definitions for sepsis and septic shock (Sepsis-3), JAMA,
doi:10.1001/jama.2016.0287
Wang, Hu, Hu, Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China, JAMA,
doi:10.1001/jama.2020.1585
Yao, Ye, Zhang, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis,
doi:10.1093/cid/ciaa237
Yazdany, Kim, Use of hydroxychloroquine and chloroquine during the covid-19 pandemic: what every clinician should know, Ann Intern Med,
doi:10.7326/M20-1334
Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)30566-3
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'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Objective</jats:title>\n'
' <jats:p>To assess the effectiveness of hydroxychloroquine in patients admitted to '
'hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Design</jats:title>\n'
' <jats:p>Comparative observational study using data collected from routine '
'care.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Setting</jats:title>\n'
' <jats:p>Four French tertiary care centres providing care to patients with '
'covid-19 pneumonia between 12 March and 31 March 2020.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Participants</jats:title>\n'
' <jats:p>181 patients aged 18-80 years with documented severe acute respiratory '
'syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive '
'care.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Interventions</jats:title>\n'
' <jats:p>Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission '
'to hospital (treatment group) versus standard care without hydroxychloroquine (control '
'group).</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Main outcome measures</jats:title>\n'
' <jats:p>The primary outcome was survival without transfer to the intensive care '
'unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory '
'distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation '
'(all at day 21). Analyses were adjusted for confounding factors by inverse probability of '
'treatment weighting.</jats:p>\n'
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' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>In the main analysis, 84 patients who received hydroxychloroquine within '
'48 hours of admission to hospital (treatment group) were compared with 89 patients who did '
'not receive hydroxychloroquine (control group). Eight additional patients received '
'hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival '
'rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and '
'75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). '
'Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, '
'0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the '
'treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of '
'patients in the treatment group had been weaned from oxygen compared with 76% in the control '
'group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the '
'treatment group (10%) experienced electrocardiographic modifications that required '
'discontinuation of treatment.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>Hydroxychloroquine has received worldwide attention as a potential '
'treatment for covid-19 because of positive results from small studies. However, the results '
'of this study do not support its use in patients admitted to hospital with covid-19 who '
'require oxygen.</jats:p>\n'
' </jats:sec>',
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