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Corresponding authors at: Department of Pneumology, Hospital Clinic of Barcelona, C/ Villarroel 170, Barcelona 08036, Spain.
Footnotes
# Authors contributed equally.
Affiliations
Center for Biomedical Research in Respiratory Diseases Network (CIBERES), Institute of Health Carlos III, Madrid, SpainDepartment of Pneumology, Hospital Clinic of Barcelona, C/ Villarroel 170, Barcelona 08036, SpainFaculty of Health Sciences, Continental University, Huancayo, Peru
Center for Biomedical Research in Respiratory Diseases Network (CIBERES), Institute of Health Carlos III, Madrid, SpainDepartment of Pneumology, Hospital Clinic of Barcelona, C/ Villarroel 170, Barcelona 08036, Spain
Center for Biomedical Research in Respiratory Diseases Network (CIBERES), Institute of Health Carlos III, Madrid, SpainTranslational Research in Respiratory Medicine, Respiratory Department, Hospital Universitari Arnau de Vilanova and Santa Maria; IRBLleida, Lleida, Spain
Corresponding authors at: Department of Pneumology, Hospital Clinic of Barcelona, C/ Villarroel 170, Barcelona 08036, Spain.
Affiliations
Center for Biomedical Research in Respiratory Diseases Network (CIBERES), Institute of Health Carlos III, Madrid, SpainDepartment of Pneumology, Hospital Clinic of Barcelona, C/ Villarroel 170, Barcelona 08036, Spain
The impact of the systemic inflammation and other aspects adding to the potential severity of patients in the SARS-CoV-2 viral dynamics are not well elucidated, particularly in critically ill patients.
Thus, we aimed to evaluate the effect of RDV on the outcomes of critically ill patients with severe COVID-19 and analyze such outcomes in certain subsets of patients to investigate whether RDV proved particularly beneficial in a particular group of critically ill patients.
Multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish ICUs between 5 February 2020 and 21 December 2021. We compared two main groups: patients receiving RDV versus those who did not receive RDV at any moment. The primary outcome was all-cause 90-day mortality. We examined outcomes according to the following categories: (1) overall population; (2) several patient subgroups based on baseline data at ICU admission: age, illness severity and organ damage (Acute Physiology and Chronic Health Evaluation [APACHE] -II and Sequential Organ Failure Assessment [SOFA] score, respectively), laboratory findings (lymphocyte count and C-reactive protein [C-RP]), respiratory support; (3) by corticosteroids therapy; (4) by SARS-CoV-2 viral load (viral RNAemia, viral antigenemia and viral RNA load [N1 region]); and (5) by RDV administration timing. To evaluate the effect of remdesivir on 90-day mortality, we used a Cox regression model stratified on the center variable, tested in univariable and propensity-adjusted multivariable analyses. A further analysis using the propensity score matching method was performed to confirm the results obtained with the propensity-adjusted multivariable model. On the other hand, effect modification by factors potentially associate with patient outcomes and remdesivir use were assessed by an interaction term. We also analysed the association between remdesivir therapy and the following variables: in-hospital and 30-day mortality (by means of a Fine-Gray competing risks model stratified on the center variable and a Cox regression model stratified on the center variable, respectively); and nosocomial bacterial pneumonia (by means of generalised estimating equations, considering a binomial distribution and accounting for the effect raised by the clustering of patients from the same center).
Among the 6225 COVID-19 patients that were admitted to 55 ICUs. We included 5004 patients in this analysis, of whom 4209 (84%) did not receive RDV and 795 (16%) received RDV during hospitalization (Fig. 1).
Ninety-day mortality rate was lower in patients who received RDV than in those who did not receive RDV (34 % vs. 29%, p = 0.012). Also, in-hospital (31 % vs. 27%, p = 0.025) and 30-day mortality (25 % vs. 18%, p<0.001) were lower in the RDV group (Supplementary Table 1). In the propensity-adjusted multivariable analysis, RDV use was not significantly associated with 90-day mortality (HR 1.00, 95% CI 0.85 to 1.17; p = 0.970), nor with in-hospital (sHR 0.94, 95% CI 0.81 to 1.09, p = 0.41) and 30-day mortality (HR 0.86, 95% CI 0.71 to 1.05, p = 0.145) (Table 1). In the analysis using the propensity score matching (777 patients received RDV and 777 did not receive RDV), the Kaplan-Meier curves showed that there was no statistical difference between both groups for 90-day mortality (p = 0.280) (Supplementary Figure 1). Furthermore, Cox regression showed that RDV use was not associated with the risk of 90-day mortality (HR 0.95, 95% CI 0.79 to 1.16; p = 0.636), nor with in-hospital mortality (sHR 0.92, 95% CI 0.76 to 1.11; p = 0.36) and 30-day mortality (HR 0.81, 95% CI 0.65 to 1.02; p = 0.075).
Table 1Association of remdesivir therapy and 90-day mortality (Panel A) and early administration of remdesivir treatment from first symptoms and 90-day mortality (Panel B).
Adjusted for variables (age, sex, body mass index, diabetes mellitus, chronic liver disease, chronic heart disease, chronic lung disease, chronic renal failure, immunosuppression, APACHE-II score at ICU admission, lymphocyte count at ICU admission, C-reactive protein at ICU admission, respiratory support at ICU admission, septic shock at ICU admission, lopinavir/ritonavir administration, tocilizumab administration, other antiviral administration, corticosteroids, COVID-19 wave and the propensity score).
APACHE-II score was assessed in 2887 patients; SOFA score in 3470 patients; lymphocyte count in 4834 patients; C-reactive protein in 4675 patients; respiratory support in 4988 patients; corticosteroids in 4956 patients; viral RNAemia in plasma in 751 patients; viral antigenemia in plasma in 735 patients; and viral RNA load in plasma (N1 region) in 751 patients.
The time of administration of remdesivir treatment from first symptoms was not available for 62 patients.
<5 days
1.65 (1.13 to 2.40)
0.009
1.53 (1.02 to 2.31)
0.042
<7 days
1.19 (0.88 to 1.60)
0.253
1.21 (0.85 to 1.72)
0.285
Abbreviations: HR indicates hazard ratio; CI, confidence interval; APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment; RNA, ribonucleic acid.
a Adjusted for variables (age, sex, body mass index, diabetes mellitus, chronic liver disease, chronic heart disease, chronic lung disease, chronic renal failure, immunosuppression, APACHE-II score at ICU admission, lymphocyte count at ICU admission, C-reactive protein at ICU admission, respiratory support at ICU admission, septic shock at ICU admission, lopinavir/ritonavir administration, tocilizumab administration, other antiviral administration, corticosteroids, COVID-19 wave and the propensity score).
b APACHE-II score was assessed in 2887 patients; SOFA score in 3470 patients; lymphocyte count in 4834 patients; C-reactive protein in 4675 patients; respiratory support in 4988 patients; corticosteroids in 4956 patients; viral RNAemia in plasma in 751 patients; viral antigenemia in plasma in 735 patients; and viral RNA load in plasma (N1 region) in 751 patients.
c Interaction effect for the subgroup and treatment group.
d Estimation failed due to numerical problem. Because the coefficients did not converge, no further models were fitted.
e Cut-off value obtained from ROC curve for 90-day mortality.
f The time of administration of remdesivir treatment from first symptoms was not available for 62 patients.
To examine mortality risk for particular types of patients, we explored modification effects by age, APACHE-II score, SOFA score, lymphocyte count, C-RP, respiratory support, corticosteroids, viral RNAemia, viral antigenemia and viral RNA load in plasma. No significant effect modification was found after adjustment for covariates using propensity score (Table 1).
Among the overall population receiving RDV, there was significant association observed between early administration (<5 days since symptoms’ onset) and the propensity-adjusted risk of 90-day mortality (HR 1.53, 95% CI 1.02 to 2.31, p = 0.042) (Table 1). In contrast, there were no significant association between <7 days since symptoms’ onset and the risk of 90-day mortality (HR 1.21, 95% CI 0.85 to 1.72, p = 0.285).
When compared to the non-RDV group, patients in the RDV group less frequently presented myocarditis, cardiac ischemia, delirium, coagulation disorder, anemia, acute renal failure and liver dysfunction (Supplementary Table 2). The propensity-adjusted analysis showed no association between RDV treatment and nosocomial bacterial pneumonia (OR 1.06, 95 CI 0.84 to 1.33, p = 0.640). In the analysis using the propensity score matching, RDV use was not associated with nosocomial bacterial pneumonia (OR 1.22, 95 CI 0.98 to 1.52, p = 0.068) (Supplementary Table 3).
In this large, multicentre study involving over five thousand critically ill patients with COVID-19 admitted to 55 Spanish ICUs, we observed that the use of RDV was not associated with an overall reduced risk of 90-day mortality, nor when analyzing by subgroup populations; patients treated with RDV overall presented longer lengths of ICU stay, which seems to be due to longer length of mechanical ventilation; early administration of RDV from symptoms’ onset was associated with a higher risk of 90-day mortality in the overall population; and patients treated with RDV showed lower significant rates of organic damage associated with severe COVID-19 such as cardiac, neurological, coagulation, renal and liver complications.
The underlying pathophysiological mechanisms associated with severe COVID-19 are not fully elucidated,
nor are therefore the tools to identify early phenotypes with high risk of developing more severe cases of COVID-19 that might potentially benefit more of early and intensive antiviral treatment.
This has become a major challenge for the scientific community, as patients developing severe COVID-19, and in particular those requiring ICU admission have poor prognosis.
might particularly benefit from RDV treatment seems to be refuted by our findings. The lack of influence of RDV on mortality independently of the viral load in plasma and the inflammatory status could reflect an inability of RDV to mediate a significant inhibitory activity of viral replication and/or clinical benefit in patients already exhibiting a large burden viral replication (both groups, RDV treated and non-treated presented to the ICU with high median levels of viral load in plasma), which in turn is associated to a strong stimulation of the innate immunity leading to exacerbated inflammation. Whether new, more specific/potent antivirals could mediate a beneficial effect in this context remains to be elucidated. Our results are in accordance of the recent published update of a living review about remdesivir in adults hospitalized with COVID-19 that confirm that remdesivir probably results in little to no difference in mortality.
Major Update 2: remdesivir for adults with COVID-19: a living systematic review and meta-analysis for the American college of physicians practice points.
A possible limitation of the propensity score methods is their inability to control for unmeasured confounding. Another limitation is the different waves of the pandemic, which could have influenced our results. We have however adjusted all of our analyses for this confounder.
In summary, treatment with RDV was not associated with improved outcomes in critically ill patients with severe COVID-19, neither overall nor when stratifying by clinically relevant variables such as age, illness severity, organ damage, laboratory findings, respiratory support or SARS-CoV-2 viral load in plasma. Moreover, RDV treatment was associated with longer lengths of ICU admission. Early administration since symptoms onset may prove harmful. Our study adds to the mounting evidence suggesting that RDV is not efficacious in treating severe COVID-19, although further studies are warranted to elucidate whether certain subsets of patients might benefit from it.
Authors' contributions
Conceptualization: CC, AM, AT; Data Curation: CC, AM, TC, Formal analysis: AG; Methodology: all authors; Investigation: CC, AM, TC, FB, AT; Project administration: CC, AM, AT; critical revision of the manuscript for important intellectual content: CC, AM, FB, and AT; and Funding acquisition: AT; Resources: CC, AM, AT; Sofware: AG; Supervision: AT; Validation:all authors; Visualization: all the authors, Writing-original draft: all authors; Writing-review and editing: CC, AM, FB, TC, AT. AThad full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript. CiberesUCICOVID consortium participated in data collection.
Funding
This study was supported by the Instituto de Salud Carlos III de Madrid (COV20/00110, ISCIII); Fondo Europeo de Desarrollo Regional (FEDER); "Una manera de hacer Europa"; and Centro de Investigación Biomédica En Red – Enfermedades Respiratorias (CIBERES). DdGC has received financial support from the Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by European Social Fund (ESF)/ “Investing in your future”. CC received a grant from the Fondo de Investigación Sanitaria (PI19/00207), Instituto de Salud Carlos III, co-funded by the European Union.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We are indebted to all participating medical and nursing colleagues for their assistance and cooperation in this study.
CIBERESUCICOVID Project Investigators: Víctor D. Gumucio- Sanguino, Rafael Mañez: Hospital Universitario de Bellvitge, Barcelona. Jordi Solé-Violan, Felipe Rodríguez de Castro: Hospital Dr. Negrín, Las Palmas. Fernando Suarez-Sipmann: Hospital Universitario La Princesa, Madrid. Ruth Noemí Jorge García, María Mora Aznar: Hospital Nuestra Señora de Gracia, Zaragoza. Mateu Torres, María Martinez, Cynthia Alegre, Jordi Riera, Sofía Contreras, Juan Manuel Pericas, Ricard Ferrer, Jordi Riera: Hospital Universitari Vall d'Hebron, Barcelona., Jesús Caballero, Javier Trujillano, Montse Vallverdú, Miguel León, Mariona Badía, Begoña Balsera, Lluís Servià, Judit Vilanova, Silvia Rodríguez, Neus Montserrat, Silvia Iglesias, Javier Prados, Sula Carvalho, Mar Miralbés, Josman Monclou, Gabriel Jiménez, Jordi Codina, Estela Val, Pablo Pagliarani, Jorge Rubio, Dulce Morales, Andrés Pujol, Àngels Furro, Beatriz García, Gerard Torres, Javier Vengoechea, David de Gonzalo-Calvo, Jessica González, Silvia Gomez: Hospital Universitari Arnau de Vilanova, Lleida. José M. Gómez: Hospital General Universitario Gregorio Marañón, Madrid. Nieves Franco: Hospital Universitario de Móstoles, Madrid. José Barberán: Hospital Universitario HM Montepríncipe. Guillermo M Albaiceta, Lorena Forcelledo Espina, Emilio García Prieto, Paula Martín Vicente, Cecilia del Busto Martínez: Hospital Universitario Central de Asturias, Oviedo. Pablo Vidal- Cortés: Complexo Hospitalario Universitario de Ourense, Ourense. José Luis García Garmendia, María Aguilar Cabello, Carmen Eulalia Martínez Fernández: Hospital San Juan de Dios del Aljarafe, Sevilla. Nieves Carbonell, María Luisa Blasco Cortés, Ainhoa Serrano Lázaro, Mar Juan Díaz: Hospital Clínic Universitari de València, Valencia. Aaron Blandino Ortiz: Hospital Universitario Ramón y Cajal, Madrid. Rosario Menendez: Hospital La Fe de Valencia. Luis Jorge Valdivia: Hospital Universitario de León, León. María Victoria Boado: Hospital Universitario de Cruces, Barakaldo. Susana Sancho Chinesta: Hospital Universitario y Politécnico La Fe, Valencia. Maria del Carmen de la Torre: Hospital de Mataro. Ignacio Martínez Varela, María Teresa Bouza Vieiro, Inés Esmorís Arijón: Hospital Universitario Lucus Augusti, Lugo. David Campi Hermoso., Rafaela Nogueras Salinas., Teresa Farre Monjo, Ramon Nogue Bou., Gregorio Marco Naya., Carme Barberà, Núria Ramon Coll: Hospital Universitari de Santa Maria, Lleida. Mercedes Catalán-González, Juan Carlos Montejo-González: Hospital Universitario 12 de Octubre, Madrid. Gloria Renedo Sanchez-Giron, Juan Bustamante-Munguira, Elena Bustamante-Munguira, Ramon Cicuendez Avila, Nuria Mamolar Herrera: Hospital Clínico Universitario, Valladolid. Raquel Almansa, Alicia Ortega, Jesús Bermejo-Martin: Instituto de Investigación Biomédica de Salamanca (IBSAL). Víctor Sagredo: Hospital Universitario de Salamanca, Salamanca. Jose Añon, Alexander Agrifoglio, Lucia Cachafeiro, Emilio Maseda: Hospital Universitario La Paz-Carlos III, Madrid. Lorenzo Socias, Mariana Andrea Novo, Albert Figueras, Maria Teresa Janer, Laura Soliva, Marta Ocón, Luisa Clar, J Ignacio Ayestarán: Hospital Universitario Son Espases, Palma de Mallorca. Yhivian Peñasco, Sandra Campos Fernández: Hospital Universitario Marqués de Valdecilla, Santander. Mireia Serra-Fortuny, Eva Forcadell-Ferreres, Immaculada Salvador-Adell, Neus Bofill, Berta Adell-Serrano, Josep Pedregosa Díaz, Núria Casacuberta-Barberà, Luis Urrelo-Cerrón, Àngels Piñol-Tena, Ferran Roche-Campo: Hospital Verge de la Cinta de Tortosa, Tortosa. Amalia Martínez de la Gándara, Pablo Ryan Murúa, Covadonga Rodríguez Ruíz, Laura Carrión García, Juan I Lazo Álvarez: Hospital Universitario Infanta Leonor,Madrid. José Ángel Lorente, Oscar Peñuelas: Hospital Universitario de Getafe. Ana Loza-Vázquez, Desire Macias Guerrero: Hospital Universitario Virgen de Valme, Sevilla. Arturo Huerta, Daniel Tognetti: Clinica Sagrada Familia, Barcelona. Carlos García Redruello, David Mosquera Rodríguez, Eva María Menor Fernández, Sabela Vara Adrio, Vanesa Gómez Casal, Marta Segura Pensado, María Digna Rivas Vilas, Amaia García Sagastume: Hospital de Vigo, Vigo. Raul de Pablo Sánchez, David Pestaña Laguna, Tommaso Bardi: Hospital Universitario Ramón y Cajal, Madrid. Rosario Amaya Villar, Carmen Gómez Gonzalez, Maria Luisa Gascón Castillo: Hospital Universitario Virgen del Rocio, Sevilla. José Garnacho-Montero, María Luisa Cantón-Bulnes: Hospital Universitario Virgen Macarena, Sevilla. Judith Marin-Corral, Cristina Carbajales Pérez: Hospital Álvaro Cunqueiro, Vigo. Joan Ramon Masclans, Ana Salazar Degracia, Judit Bigas, Rosana Muñoz-Bermúdez, Clara Vilà-Vilardel, Francisco Parrilla, Irene Dot, Ana Zapatero, Yolanda Díaz, María Pilar Gracia, Purificación Pérez, Andrea Castellví, Cristina Climent: Hospital del Mar, Barcelona. Lidia Serra, Laura Barbena, Iosune Cano: Consorci Sanitari del Maresme, Barcelona. Pilar Ricart, Alba Herraiz, Pilar Marcos, Laura Rodríguez, Maria Teresa Sariñena, Ana Sánchez: Hospital Universitari Germans Trias i Pujol, Badalona. Alejandro Úbeda: Hospital Punta de Europa, Algeciras. María Cruz Martin Delgado: Hospital Universitario Torrejón-Universidad Francisco de Vitoria, Madrid. Elena Gallego, Juan Fernando Masa Jimenez: Hospital Universitario San Pedro de Alcántara, Cáceres. Gemma Gomà, Emi Díaz: Hospital Parc Taulí, Sabadell. Mercedes Ibarz, Diego De Mendoza: Hospital Universitari Sagrat Cor, Bacelona. Enric Barbeta, Victoria Alcaraz-Serrano, Joan Ramon Badia, Manuel Castella, Leticia Bueno, Adrian Ceccato, Andrea Palomeque, Laia Fernandez Barat, Catia Cillóniz, Pamela Conde, Javier Fernández, Albert Gabarrus, Karsa Kiarostami, Alexandre López- Gavín, Cecilia L Mantellini, Carla Speziale, Nil Vázquez, Hua Yang, Minlan Yang, Carlos Ferrando, Pedro Castro, Marta Arrieta, Jose Maria Nicolas, Rut Andrea: Hospital Clinic, Barcelona. Marta Barroso, Raquel Pérez, Sergio Álvarez, Dario Garcia-Gasulla, Adrián Tormos: Barcelona supercomputing Center, Barcelona. Luis Tamayo Lomas, Cesar Aldecoa, Rubén Herrán-Monge, José Ángel Berezo García, Pedro Enríquez Giraudo: Hospital Rio Hortega, Valladolid. Pablo Cardinal Fernández, Alberto Rubio López, Orville Báez Pravia: Hospitales HM, Madrid. Juan López Messa, Leire Pérez Bastida, Antonjo Alvarez Ruiz: Complejo Asistencial Universitario de Palencia, Palencia. José Trenado, Anna Parera Pous: Hospital Universitari MutuaTerrassa, Terrassa. Cristóbal Galbán, Ana López Lago, Eva Saborido Paz, Patricia Barral Segade: Hospital de Santiago de Compostela, Santiago. Ana Balan Mariño, Manuel Valledor Mendez: Hospital San Agustin, Aviles. Raúl de Frutos, Luciano Aguilera: Hospital Basurto, Basurto. Felipe Pérez-García, Esther López-Ramos, Ángela Leonor Ruiz-García, Belén Beteré: Hospital Universitario Principe Asturias, Alcala de Henares. Rafael Blancas: Hospital Universitario del Tajo, Aranjuez. Cristina Dólera, Gloria Perez Planelles, Enrique Marmol Peis, Maria Dolores Martinez Juan, Miriam Ruiz Miralles, Eva Perez Rubio, Maria Van der Hofstadt Martin-Montalvo, Ángel Sánchez-Miralles, Tatiana Villada Warrington: Hospital Universitario Sant Joan d'Alacant, Alicante. Juan Carlos Pozo-Laderas: Hospital Universitario Reina Sofia. Angel Estella, Sara Guadalupe Moreno Cano: Hospital de Jerez, Jerez. Federico Gordo: Hospital Universitario del Henares, Coslada. Basilisa Martinez Palacios: Hospital Universitario Infanta Cristina, Parla. Maite Nieto, Maria Teresa Nieto: Hospital de Segovia, Segovia. Sergio Ossa: Hospital de Burgos, Burgos. Ana Ortega: Hospital Montecelo, Pontevedra. Miguel Sanchez: Hospital Clinico, Madrid. Bitor Santacoloma: Hospital Galdakao, Galdakao.
Ethics approval and consent to participate
The study received approval by the Hospital Clínic de Barcelona Institutional Review Board (Comité Ètic d'Investigació Clínica, registry number HCB/2020/0370), and either patients or their relatives provided informed consent. All participating hospitals obtained local ethics committee approval.
Major Update 2: remdesivir for adults with COVID-19: a living systematic review and meta-analysis for the American college of physicians practice points.
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