Impact of Azithromycin and/or Hydroxychloroquine on Hospital Mortality in COVID-19
Filippo Albani, Federica Fusina, Alessia Giovannini, Pierluigi Ferretti, Anna Granato, Chiara Prezioso, Danilo Divizia, Alessandra Sabaini, Marco Marri, Elena Malpetti, Giuseppe Natalini
Journal of Clinical Medicine, doi:10.3390/jcm9092800
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to widespread use of hydroxychloroquine and azithromycin despite the lack of conclusive evidence for their safety and efficacy. We evaluated the association between treatment with hydroxychloroquine and/or azithromycin and hospital mortality as the primary outcome. We compared the hospital mortality of patients treated with hydroxychloroquine alone, azithromycin alone, or their combination to the mortality of patients who received neither drug. A logistic multivariate model with overlap weight propensity score was used for estimation of odds ratios (ORs) with 95% confidence intervals (95% CIs). One thousand four hundred and three patients with SARS-CoV-2 infection were admitted to the hospital. At the time of the analysis, the outcome was available for 1376 (98%) of them. Five hundred and eighty-seven patients (42%) received azithromycin and 377 patients (27%) received hydroxychloroquine, alone or in combination. In-hospital mortality was 26%. After the adjusted analysis, azithromycin alone was associated with lower mortality (OR 0.60, 95% CI 0.42-0.85) compared to no treatment. Hydroxychloroquine alone (OR 0.76, 95% CI 0.53-1.08) and the combination of azithromycin and hydroxychloroquine (OR 1.13, 95% CI 0.77-1.69) were not associated with hospital mortality. In this cohort of patients, azithromycin alone was associated with lower hospital mortality but hydroxychloroquine was not associated with increased or reduced mortality. While we await randomized clinical trials, these data support the use of azithromycin in novel coronavirus disease 2019 (COVID-19) and can contribute to better understanding of its role in further meta-analyses.
Conflicts of Interest: The authors declare no conflict of interest.
References
Borba, Val, Sampaio, Alexandre, Melo et al., Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2020.8857Boulware, Pullen, Bangdiwala, Pastick, Lofgren et al., A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2016638Chorin, Wadhwani, Magnani, Dai, Shulman et al., QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin, Heart Rhythm,
doi:10.1016/j.hrthm.2020.05.014Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial, Int. J. Antimicrob. Agents,
doi:10.1016/j.ijantimicag.2020.105949Geleris, Sun, Platt, Zucker, Baldwin et al., Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2012410Gielen, Johnston, Edwards, Azithromycin induces anti-viral responses in bronchial epithelial cells, Eur. Respir. J,
doi:10.1183/09031936.00095809Grasselli, Zangrillo, Zanella, Antonelli, Cabrini et al., Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy, JAMA,
doi:10.1001/jama.2020.5394Kalil, Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics, JAMA,
doi:10.1001/jama.2020.4742Kissler, Tedijanto, Goldstein, Grad, Lipsitch, Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period, Science,
doi:10.1126/science.abb5793Madrid, Panchal, Warren, Shurtleff, Endsley et al., Evaluation of Ebola Virus Inhibitors for Drug Repurposing, ACS Infect. Dis,
doi:10.1021/acsinfecdis.5b00030Mehra, Ruschitzka, Patel, Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis, Lancet,
doi:10.1016/S0140-6736(20)31324-6Peduzzi, Concato, Kemper, Holford, Feinstein, A simulation study of the number of events per variable in logistic regression analysis, J. Clin. Epidemiol,
doi:10.1016/S0895-4356(96)00236-3Retallack, Lullo, Arias, Knopp, Laurie et al., Zika virus cell tropism in the developing human brain and inhibition by azithromycin, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.1618029113Rosenberg, Dufort, Udo, Wilberschied, Kumar et al., Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State, JAMA
Thomas, Li, Pencina, Overlap Weighting: A Propensity Score Method That Mimics Attributes of a Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.7819Thomas, Li, Pencina, Using Propensity Score Methods to Create Target Populations in Observational Clinical Research, JAMA,
doi:10.1001/jama.2019.21558Touret, Gilles, Barral, Nougairède, Van Helden et al., In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication, bioRxiv,
doi:10.1038/s41598-020-70143-6Vanderweele, Ding, Sensitivity Analysis in Observational Research: Introducing the E-Value, Ann. Intern. Med,
doi:10.7326/M16-2607Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Wu, Mcgoogan, Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention, JAMA,
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'abstract': '<jats:p>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to '
'widespread use of hydroxychloroquine and azithromycin despite the lack of conclusive evidence '
'for their safety and efficacy. We evaluated the association between treatment with '
'hydroxychloroquine and/or azithromycin and hospital mortality as the primary outcome. We '
'compared the hospital mortality of patients treated with hydroxychloroquine alone, '
'azithromycin alone, or their combination to the mortality of patients who received neither '
'drug. A logistic multivariate model with overlap weight propensity score was used for '
'estimation of odds ratios (ORs) with 95% confidence intervals (95% CIs). One thousand four '
'hundred and three patients with SARS-CoV-2 infection were admitted to the hospital. At the '
'time of the analysis, the outcome was available for 1376 (98%) of them. Five hundred and '
'eighty-seven patients (42%) received azithromycin and 377 patients (27%) received '
'hydroxychloroquine, alone or in combination. In-hospital mortality was 26%. After the '
'adjusted analysis, azithromycin alone was associated with lower mortality (OR 0.60, 95% CI '
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'associated with lower hospital mortality but hydroxychloroquine was not associated with '
'increased or reduced mortality. While we await randomized clinical trials, these data support '
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