The main results of the present study are the following: remdesivir treatment was associated with a reduced risk to develop severe ARDS in need of intubation and in-hospital mortality. The increased risk of remdesivir-induced bradycardia seems to be not associated with worst outcome.

Among our real-world population including patients with non-severe COVID-19, remdesivir reduced the risk of severe ARDS in need of intubation by 50%; this finding was consistent with results from a Canadian randomized control trial, including 1884 patients randomized to receive remdesivir, which showed a reduction by 47% for the risk of mechanical ventilation [4]. A recent Cochrane systematic review, including five RCTs with 3886 participants randomized to receive remdesivir, concluded that remdesivir may decrease the risk of new need for invasive mechanical ventilation by 44% within 28 days when compared to placebo or standard care [5]. Remdesivir treatment benefit seems to be linked to the prevention of disease progression, suggesting an added value for patients with a less severe disease or at increased risk.

Regarding in-hospital mortality, the effects of remdesivir among hospitalized COVID-19 patients are still debated. Lee et al. in a recent meta-analysis including 10,751 patients from 8 randomized control trials showed a high probability, about 94%, that remdesivir reduces mortality for non-ventilated patients with COVID-19 requiring supplemental oxygen therapy [6]; by contrast, two previous meta-analyses did not show this result [7, 8]. These contrasting results may be explained by baseline different clinical characteristics, including age and disease severity, across the trials’ populations; moreover, it should be noted that in the early phase of the COVID-19 pandemic, patients were less likely to be vaccinated, as well as to receive treatment to reduce adverse outcomes (steroids, anticoagulation, monoclonal antibodies, and immunomodulatory therapies). In our study population, we showed that remdesivir treatment was associated with a reduction by 82% of in-hospital mortality compared to a PSM control group. The beneficial effect of remdesivir compared to standard care on morality has been previously showed only in the subgroup with low‐flow oxygen at baseline [9]. A recent matched case–control study, analyzing the use of remdesivir in severe and critical hospitalized patients, showed a survival benefit in comparison with controls, limited to patients on low-flow oxygen support; in contrast, the survival benefit was not present among patients who received the drug while on high-flow oxygen therapy or mechanical ventilation [10]. It is possible that the improvement in mortality outcome, at least partially, derives from the reduced disease progression requiring more invasive ventilation, which have been previously associated with worse clinical outcome [11].

Differently from previous reports which showed an overall incidence of sinus bradycardia following remdesivir ranging from 47 to 74% [12, 13], we reported a low prevalence of remdesivir-induced bradycardia, about 20%. These differences may be explained by the different definitions (heart rate < 60 beats/min or < 50 beats/min) and diagnoses (telemetry or ECG) across the studies [12, 13].

A recent large cohort study showed that bradycardia occurs up to 16.8% of severe/critical patients on day 5 of remdesivir use; it might reflect more favorable disease course and has a substantial potential for improving prognostication of patients with COVID-19 [14].

Remdesivir-related incident sinus bradycardia might be due to its status of nucleoside analog that resembles ATP, justifying its negative reversible chronotropic effect on sinus node cells [15, 16]. According to our findings, the incident sinus bradycardia following remdesivir administration did not seem to impact on patients’ prognosis in terms of intensive care unit admission and in-hospital mortality. Our results, despite the limitation of potential confounding factors, support a safe use of remdesivir among patients with COVID-19 in a real-world setting.