To the best of our knowledge, this study provides the largest picture on mortality after the remdesivir treatment of SARS-Cov2 pneumonia in the real-world practice. The results are based on the analysis of a national registry-based cohort, filled by all Italian hospitals during the second wave of the COVID-19 pandemic.
The reimbursement of remdesivir by the Italian NHS was granted according to eligibility criteria reflecting the same grading of patient’s clinical status at hospital admission as in ACTT-1 (i.e.: having rank 5 in ordinal scale at hospital admission: pneumonia requiring supplemental low-flow oxygen therapy) . The AIFA’s RR was developed to both address the distribution across the country and obtain data on the local delivery of remdesivir from national stocks.
The overall findings evidence a dramatic effect of age on mortality, with older patients (≥ 65 years) having about 14 times higher death risk than those aged less than 40.
The estimate of mortality by day 29 observed among patients in the age group of 40–65 years [i.e.: an adjusted mortality rate of 3.5% (95% CI 3.0%-4.0%)] appears to be almost the same as that reported in the remdesivir arm of the ACTT-1 trial [4.0% (95% CI 2.1%-7.5%), among patient subgroup having the 5 rank in ordinal scale] . However, the overall estimate of mortality after remdesivir treatment in Italy by day 29 is equal to 11.7%, higher than that observed in the aforementioned randomized trial . This might be due to the older age of patients enrolled in the AIFA's RR (66.3 years on average) than that recorded in the ACTT-1 trial (58.6 years on average). Indeed, 45.4% (7469) of Italian patients were less than 65 years old, against 65.4% of ACTT-1 trial patients . An increased mortality likely connected to higher age was also reported by Frost and collagues . At the date of this analysis, the overall mortality rate in Italy of unselected hospitalized COVID − 19 patients, older than 65 years and admitted in non-intensive care units was estimated to be 31.8% (see Supplementary Table 2 in appendix). This estimate was obtained using the data available from the COVID-19 integrated national surveillance by Italian Health Institute (see Supplementary Table 1 in appendix) . Additionally, the overall mortality after remdesivir treatment in Italy appeared to be slightly higher than that observed in the WHO Solidarity Trial (i.e.: 9.4%, in the subgroup of patient not requiring ventilation at randomization) . Again, in the WHO Solidarity Trial the proportion of patients aged less than 70 years was 81.8%, while in the AIFA’s RR it was 57.5%.
The present study also registered an adjusted lower mortality among females than among males. This finding was also observed in a previous population-based cohort of hospitalised Italian patients, performed after the first pandemic wave and before the introduction in Italy of remdesivir .
Some limitations of this analysis are represented by the absence of information on comorbidities and concomitant treatments during hospitalization. Actually, high number of comorbidities, regardless of age group, was found to strongly predict mortality among COVID-19 patients in Italy . However, In the ACTT-1 trial more than 50% of patients had two or more comorbidities and only 18% had none. . As for concomitant therapies, we expect that almost all patients in our cohort received also a corticosteroid treatment, according to current guidelines and AIFA recommendations . Instead, in the ACTT-1, during the study period, only 23.0% of patients received a concomitant corticosteroid treatment .
Although randomized controlled trials have long been considered to be the unique source of data on the effects of treatments, the registry-based studies are among the alternative options having several strengths from the point of view of public health . Furthermore, during the last decade both EMA and FDA increasingly approved products for new therapeutic indications without any controlled trial , or using comparisons with external controls .
With regard to remdesivir, two large randomized controlled trials (i.e. the ACTT-1 and the Solidarity trial) provided overall conflicting evidence on efficacy [6–7]. This registry-based study is the largest one obtained in a real-word context that provides evidence on mortality in hospitalized patients with laboratory confirmed COVID-19, after remdesivir treatment of pneumonia. Besides showing a clear relation between mortality and age, it also argues for efficacy of remdesivir in reducing mortality in patients older than 65 years when compared to an estimate obtained using data from the COVID-19 integrated national surveillance by Italian Health Institute. This study provides evidence on mortality after remdesivir treatment in the real-world context, for the treatment of pneumonia in hospitalized patients with laboratory confirmed COVID-19, that may address public health decision-making and it may provide data useful for designing future randomized trials.