Treatment for COVID-19—a cohort study from Northern Italy
Lorenzo Guglielmetti, Daniela Aschieri, Irina Kontsevaya, Francesco Calabrese, Alessandra Donisi, Alberto Faggi, Patrizia Ferrante, Elisa Fronti, Laura Gerna, Maria Cristina Leoni, Franco Paolillo, Giovanna Ratti, Alessandro Ruggieri, Daria Sacchini, Marta Scotti, Caterina Valdatta, Marco Stabile, Gloria Taliani, Mauro Codeluppi
Scientific Reports, doi:10.1038/s41598-021-00243-4
Multicentre, retrospective cohort study with multivariable Cox proportional-hazards modelling and survival-time inverse-probability-weighting, evaluating the impact of different treatments on survival of proven COVID-19 patients admitted to two Hospitals in the province of Piacenza, Italy. Use of tocilizumab and of high doses of low molecular weight heparin, but not of antivirals (either alone or in combination), azithromycin, and any corticosteroid, was independently associated with lower mortality. Our results support further clinical evaluation of high doses of low molecular weight heparin and tocilizumab as COVID-19 therapeutics. Italy was struck by the first epidemic wave of coronavirus disease 2019 (COVID-19) in early 2020 1 . Overall, about 44 000 excess deaths occurred in this 3-month period 2 , largely concentrated in Northern Italy. At that time, virtually no evidence was available on the optimal management of COVID-19. In this study, we aim to evaluate the impact of the medical interventions on survival in hospitalized COVID-19 patients in the province of Piacenza, Italy.
Methods A multicentre, retrospective cohort study was performed among patients hospitalized for COVID-19 from February 21st (date of the first reported COVID-19 case) to May 15th, 2020, at two Hospitals in the province of Piacenza: Guglielmo da Saliceto and Castel San Giovanni. Data for consecutive patients were extracted from electronic medical files, cross-checked, and collated in an anonymized database. Data were censored on June 30th, 2020. Adult (18 years and older) confirmed COVID-19 cases with SARS-CoV-2 reverse transcriptase realtime polymerase chain reaction test on nasal/pharyngeal swab 3 were included. Part of the cohort was described previously 4 . The study was approved by the local Ethics Committee (Area Vasta Emilia Nord), which waived the requirement for informed consent. Continuous data were presented as median and interquartile range (IQR), categorical data as counts and proportions. Low molecular weight heparin was defined as high-dose (HD-LMWH) when given at therapeutic posology (i.e. enoxaparin 6000 international units daily or more) according to drug package inserts. Prescription of treatment (including the choice of the drug and its posology) was heterogeneous in terms of indication as little evidence and no specific recommendations on their use were available. Missing data were handled with multiple imputation using chained equations with 10 imputed datasets. The proportion of missing observations ranged between 0 and 9%. Multivariable Cox proportional-hazards models were used to assess the association of treatment variables with survival, controlling for potential confounders chosen according to univariate results and a priori plausibility. Two models were used: (1) including a variable coding for treatment with any antiviral drug, and (2) including variables coding for the use of hydroxychloroquine, protease inhibitors,
Author contributions L.G. made a substantial contribution to the conception and design of the work, to the acquisition, analysis and interpretation of data for the work, performed statistical analysis, wrote the manuscript, critically revised the manuscript for important intellectual content, gave final approval of the current version to be published, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. D.A. made a substantial contribution to the conception of the work, to the acquisition, analysis and interpretation of data for the work, wrote the manuscript, critically revised the manuscript for important intellectual content, gave final approval of the current version to be published, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. I.K. made a substantial contribution to the analysis and interpretation of data for the work, wrote the manuscript, critically revised the manuscript for important intellectual content, gave final approval of the current version to be published, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. G.T. and M.C. made a substantial..
References
Alicandro, Remuzzi, Vecchia, Italy's first wave of the COVID-19 pandemic has ended: No excess mortality in May, Lancet Elsevier
Beigel, Remdesivir for the treatment of Covid-19-final report, N. Engl. J. Med
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Guglielmetti, Chiesi, COVID-19 in Italy -Passing through bitter waters, European Respiratory Society
Guglielmetti, Kontsevaya, Leoni, Severe COVID-19 pneumonia in Piacenza, Italy -a cohort study of the first pandemic wave, J. Infect. Public Health
Jonmarker, Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients, Crit Care
Nadkarni, Mortality, Bleeding and Pathology Among Patients Hospitalized with COVID-19: A Single Health System Study, J Am Coll Cardiol
Parr, Time to reassess Tocilizumab's role in COVID-19 pneumonia, JAMA Intern. Med
Who, Global surveillance for COVID-19 caused by human infection with COVID-19 virus
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"abstract": "<jats:title>Abstract</jats:title><jats:p>Multicentre, retrospective cohort study with multivariable Cox proportional-hazards modelling and survival-time inverse-probability-weighting, evaluating the impact of different treatments on survival of proven COVID-19 patients admitted to two Hospitals in the province of Piacenza, Italy. Use of tocilizumab and of high doses of low molecular weight heparin, but not of antivirals (either alone or in combination), azithromycin, and any corticosteroid, was independently associated with lower mortality. Our results support further clinical evaluation of high doses of low molecular weight heparin and tocilizumab as COVID-19 therapeutics.</jats:p>",
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