Discussion
This retrospective study of a large cohort of hospitalized patients with COVID-19 treated with remdesivir in a large healthcare system highlights several noteworthy observations. First, one in five hospitalized patients with COVID-19 improved clinically prior to completion of the 5-day course of remdesivir treatment. Second, there was a higher rate of hospital re-admission or ED visit among those who were dismissed prior to completion of the standard 5-day course of remdesivir. Third, mortality at day 28 was associated with older age and having not completed the 5-day course of remdesivir. As the COVID-19 pandemic established endemicity worldwide, our clinical observations have potential applications in its management across the continuum of care settings.
Our study examined all hospitalized patients with COVID-19 treated with remdesivir from November 2020 to November 2021, a period that encompasses the pre-vaccination period to the sequential roll out of vaccines to eligible patients.11,12 Among our cohort of >3,000 patients, the mortality rate was 8.7%; this reflects the high-risk characteristics of our population. Our patients are predominantly older (56% are older than 65 years old) and had multiple medical comorbidities (as measured by MASS). Hypertension, cardiovascular disease and diabetes were the most common underlying conditions. While medical comorbidities have been associated with severe outcomes from COVID-19, an older age was the most significant risk factor for all-cause and COVID-19 related death in this study.13 The significant association between older age and severe outcome from COVID-19 is well described.14-16 Since the conduct of our study, there has been increasing rates of vaccination among the population, while treatment options have expanded to reduce the risk of death and severe disease from COVID-19.
In our cohort, one in five patients who required hospitalization for COVID-19 improved early prior to completion of the standard 5-day remdesivir treatment. This is a novel observation that has important clinical, operational and logistical implications. During the different waves of the COVID-19 pandemic, especially during the SARS-CoV-2 Delta wave, healthcare systems were overburdened with high number of patients requiring medical care in the hospital. This resulted in a shortage of medical beds and staff to care for the sick hospitalized patients. In this situation, one wonders if patients who have improved but have not yet completed the remdesivir course could be safely dismissed from the hospital. Because of the uncertainty of their outcomes, our program established hospital-based outpatient infusion centers to allow for hospital dismissal of stable and improving patients yet provided the infrastructure to complete the treatment course. This strategy is akin to well-established outpatient antimicrobial therapy (OPAT) programs, where intravenous antibiotics are administered in infusion units outside the hospital settings. As a result of this practice, we estimated a total of 1077 hospital rooms that were made available to other patients needing critical services in the hospital.
This study observed that the rate of death by day 28 among patients who did not complete 5-day course of remdesivir were higher compared to those who completed the treatment course. In particular, patients who did not complete remdesivir course in the hospital and did not receive additional dose of remdesivir as an outpatient had three-time higher odds of death within 28 days compared to patients who completed the treatment course. Our findings imply that completion of a planned 5-day course of remdesivir is crucial to improving outcomes. Physical and electronic infrastructures to ensure the administration of intravenous remdesivir in the outpatient setting is therefore important. The implementation of our strategy was intertwined with the establishment of the Monoclonal Antibody Treatment (MATRx) Program in November 2020.17 Since the infrastructure of outpatient remdesivir infusion was operational since November 2020, it was an easy transition for our program to provide remdesivir as an approved option for outpatients with mild to moderate COVID-19. Our program have used the three-day outpatient remdesivir course especially among those with contraindications to ritonavir-boosted nirmatrelvir and when there is scarcity of effective anti-spike neutralizing monoclonal antibodies.10
Despite the benefits of early dismissal (by allowing patients to recover in the comfort of their home environment), it is important to point out that there was a higher rate of re-admissions or ED visits among patients who were dismissed early to complete remdesivir in the outpatient setting. While it is possible that clinically improving patients have been prematurely dismissed, the biphasic course of COVID-19 could have prompted patients to seek further care when their symptoms rebounded.18 This data further calls into question the assumptions that patients with COVID-19 selected for hospital dismissal are well enough that ongoing medical care, including medication therapy, is unneeded. It is therefore important to remotely monitor these patients at home, in order to capture early warning signs that would require further medical intervention.19 It will also be important to further characterize these patients and define risk factors for re-admissions in order to mitigate the need for further medical evaluations.
There are several limitations of this study. First, it is a retrospective study with inherent deficiencies in capturing all clinically relevant information for all patients. Second, the cohort was stratified patients into four groups, with varying demographic and clinical characteristics. We attempted to adjust for them in the multivariable analysis. Third, the findings may only apply to healthcare systems with the infrastructure that allows for the safe administration of remdesivir in the outpatient setting. While our program adapted this novel strategy in conjunction with the implementation of anti-spike monoclonal antibody infusion, the logistics of scheduling once daily doses of remdesivir for patients was challenging (but not impossible) to implement. It will be important to assess the economic impact of this practice as well as patient perception and satisfaction of this strategy of care.
This study of over 3000 patients hospitalized for COVID-19 highlights the importance of completing a 5-day course of remdesivir treatment. Older age was significantly associated with a higher risk of death, while completion of the full course of remdesivir was associated with lower risk of death. Among patients who have improved clinically to allow for early hospital dismissal, it is important to ensure that they complete their treatment course in the outpatient setting. This novel strategy of transitioning remdesivir treatment among hospitalized patients from inpatient to the outpatient setting appears to be associated with clinical benefits, in addition to decongesting an overburdened hospital system. This strategy could be implemented selectively among stable patients, especially when hospitals are overburdened with a census exceeding their capacity for care.