key: cord-0329261-tfo3m3uf authors: Russo, A.; Binetti, E.; Borrazzo, C.; Gentilini Cacciola, E.; Battistini, L.; Ceccarelli, G.; Mastroianni, C. M.; d'Ettorre, G. title: Efficacy of remdesivir-containing therapy in hospitalized COVID-19 patients: a prospective clinical experience date: 2021-07-07 journal: nan DOI: 10.1101/2021.07.01.21259852 sha: cc1bd470879861575de620465d18bdfbfbf59077 doc_id: 329261 cord_uid: tfo3m3uf Objectives: remdesivir is currently approved for the treatment of COVID-19. The recommendation for using remdesivir in COVID-19 was based on the in vitro and in vivo activity of this drug against SARS-CoV-2. Methods: this was a prospective, observational study conducted on a large population of patients hospitalized for COVID-19. The primary endpoint of the study was to evaluate the impact of remdesivir-containing therapy on 30-day mortality; secondary endpoint was the impact of remdesivir-containing therapy on the need of high flow oxygen therapy (HFNC) or non-invasive ventilation (NIV) or mechanical ventilation. Data were analyzed after propensity score matching. Results: 407 patients with SARS-CoV-2 pneumonia were consecutively enrolled. Out of these, 294 (72.2%) and 113 (27.8%) were respectively treated or not with remdesivir. Overall, 61 (14.9%) patients were treated during hospitalization with non-invasive or mechanical ventilation, while a 30-day mortality was observed in 21 (5.2%) patients. Cox regression analysis, after propensity score matching, showed that therapies, including remdesivir-containing therapy, were not statistically associated with 30-day survival or mortality, while need of HFNC/NIV (HR 17.921, CI95% 0.954-336.73, p=0.044) and mechanical ventilation (HR 3.9, CI95% 5.36-16.2, p=0.003) resulted independently associated with 30-day mortality. Finally, therapies including or not remdesivir were not independently associated with lower or higher risk of HFNC/NIV or mechanical ventilation. Conclusions: this real-life experience about the remdesivir use in hospitalized patients with COVID-19 was not associated with significant increase in rates of survival or reduced use of HFNC/NIV or mechanical ventilation, compared to patients treated with other therapies not including remdesivir. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is identified as the cause 58 of an outbreak of respiratory illness, evolving in a pandemic. The virus causes respiratory illness 59 and can rapidly spread from person to person; then, in a large number of patients this virus causes 60 coronavirus diseases (COVID-19) characterized by pneumonia, severe acute respiratory syndrome, 61 kidney failure, and a significant rate of mortality [1- [2] [3] . 62 To date, treatment of critically ill infected patients is primarily supportive with a robust 63 evidence reported in literature about the use of steroids, especially dexamethasone, in lowering 64 mortality especially in critically ill patients [4] ; some important evidence suggests also the role of 65 low-molecular-weight heparin (LMWH) to reduce in-hospital mortality [5] . 66 As a matter of fact, only remdesivir was currently approved for the treatment of COVID-19. 67 The recommendation for using remdesivir as treatment of COVID-19 is based on the in vitro and in 68 vivo activity of remdesivir against SARS-CoV-2 [6] . Moreover, remdesivir showed an acceptable 69 safety profile and exhibits in vivo prophylactic and therapeutic efficacy against SARS-CoV-2 70 infection [7] . 71 According to randomized clinical trials, its administration might shorten the time to 72 recovery and reduce severity of infection in adults hospitalized with COVID-19 [8] . However, there 73 are still many ongoing clinical trials and more evidence is needed to confirm the efficacy of 74 remdesivir in treating patients with COVID-19 at different stages of severity. in-hospital mortality of 11%. 89 In Other treatments used in COVID-19 patients were reported in Table 2 . Comparison between 99 patients treated or not with remdesivir showed that steroids (93% Vs 81%, p<0.001), LMWH (93% 100 Vs 52%, p<0.001) were more frequently prescribed in remdesivir group. Antibiotic therapy (58% 101 or not with remdesivir before (p=0.24) and after (p=0.07) propensity score matching, reporting no 108 differences between the 2 study groups. Standardized differences before and after propensity score 109 matching were reported in supplementary Figure 1 Multivariate Cox regression analysis about 30-day mortality after propensity score matching 111 was reported in Table 3 ventilation was analyzed after propensity score matching (see Table 4 ). Data showed that 117 comorbidities and therapies, including remdesivir-containing regimen, were not independently 118 associated with a lower or higher risk of HFNC/NIV or mechanical ventilation. severe COVID-19 [10] . In this study, significantly lower mortality was observed in those treated 148 with remdesivir (7.6%) compared with the non-remdesivir-cohort patients (12.5%). Conversely, 149 data from Solidarity trial, conducted in 30 countries [11] , showed no decrease of in-hospital 150 mortality in patients treated with remdesivir, with the important limitation that other outcomes, 151 clinical improvement and adverse events, were non carefully evaluated. 152 Some important meta-analysis showed that COVID-19 patients receiving remdesivir had 153 significantly higher rates of recovery and hospital discharge with lower rates of developing serious 154 adverse events compared to patients receiving standard of care/placebo [12] [13] . However, these 155 analyses confirmed that no significant differences were observed about clinical improvement and 156 rate of mortality during hospitalization. Specifically, mortality was the main outcome reported in all 157 included studies, and none of the studies showed significant decrease of mortality also if they were 158 not adequately powered for mortality outcome [12] . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. [17] . 236 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.01.21259852 doi: medRxiv preprint Remdesivir was administrated, after written informed consent, to patients with the following 237 characteristics: pneumonia, less than 10 days from the onset of symptoms, no need for HFNC or 238 NIV or mechanical ventilation, alanine aminotransferase no more than 5 times the upper limit of the 239 reference range, estimated glomerular filtration rate (eGFR) greater than 30 mL/minute. A 5-day 240 regimen was prescribed in all cases. Patients without these criteria were not eligible for remdesivir 241 All patients were followed-up until discharge or death. 243 244 The primary endpoint of the study was to evaluate the impact of remdesivir-containing 246 therapy on 30-day mortality in hospitalized patients with SARS-CoV2 pneumonia. Secondary 247 endpoint was the impact of remdesivir-containing therapy on the need of NIV or mechanical 248 To reduce the impact of treatment-selection bias in the estimation of treatment effects, 250 propensity score matching was conducted. Variables were selected for inclusion in the propensity 251 score based on potential impact on receipt of remdesivir and association with mortality [18]. The 252 variables included were steroids, antibiotics (excluding macrolides), age, gender, and the use of 253 LMWH during hospital admission. A propensity score density plot and Love plot were generated to 254 examine the balance of propensity score and covariate distribution between the two groups (see 255 supplementary Figure 1) . 256 To evaluate demographic factors, Welch's t tests assuming unequal variances were used for 257 continuous independent variables, while Pearson Chi-square or Fisher's Exact Test when 258 appropriate were used for categorical variables. Welch's analysis of variance (ANOVA) was used 259 to assess group differences for continuous outcome. Welch's t-tests assuming unequal variances 260 were used for post-hoc comparisons. 261 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.01.21259852 doi: medRxiv preprint All tests will be two-tailed, and a p-value of <0.05 were considered statistically significant. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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