A Propensity Score–Matched Observational Study Of Remdesivir in Patients With COVID-19 And Severe Kidney Disease Ⅱ
Nov 30, 2023
Discussion
In this retrospective cohort study, we examined the risk of clinical and laboratory adverse events in hospitalized patients with COVID-19 who had eGFR ,30 ml/min per 1.73 m2 and received remdesivir compared with historical controls who were hospitalized prior to EUA for remdesivir. This is the first report that used matched historical comparators with eGFR ,30 ml/min per 1.73 m2 . Our PS-matched algorithm was designed to predict both the chances of receiving remdesivir and the chances of adverse in-hospital outcomes (22). Our study also included a detailed chart review to ensure accurate matching on appropriate indicators of the severity of illness bolstered by a comprehensive review of all physicians and nursing notes by two physicians for both patients and matched controls to ensure rigorous capture and adjudication of predefined adverse events.
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We found no significant difference in key clinical adverse events of interest. Lowest hemoglobin and highest AST and ALT values were similar between remdesivir-treated patients and historical comparators, whereas hyperglycemia was more common in remdesivir-treated patients. The rate of hyperglycemia was extremely high in the cohort treated with remdesivir; however, 81% of these patients also concurrently received dexamethasone compared with 10% of historical control patients. This is because all control patients were admitted in March or April 2020, prior to the routine use of dexamethasone for COVID-19 at our center. This change in the standard of care occurred in June 2020 with the release of data from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, after which hospitalized patients with severe COVID-19 routinely received dexamethasone (23). Our study was not powered to show treatment effectiveness, and the finding of insignificantly improved mortality in redeliver-treated patients must be considered in light of the changing standard of care for COVID-19 over the study period and the known improvement in in-hospital mortality over time among hospitalized patients with COVID-19 (24)
Figure 2. | Percentage of patients experiencing clinical events of interest. Clinical outcomes were adjudicated by two physicians who reviewed each physician and clinical nursing note for the 5-day remdesivir course 148 hours after remdesivir treatment (black bars) and the first 7 days of admission for historical comparators (gray bars). The only clinical event that was significantly increased in patients treated with remdesivir was the incidence of hyperglycemia (defined by glucose .200), which occurred in 81% of patients treated with remdesivir compared to 55% of controls. A total of 25 of 31 (81%) remdesivir-treated patients also received dexamethasone concurrently compared with three of 31 (10%) controls. Among the six remdesivir-treated patients who did not receive dexamethasone, three (50%) also had hyperglycemia .200 mg/dl. There were no significant differences in any of the other adverse events. ALT, alanine aminotransferase; AST, aspartate aminotransferase; HGB, hemoglobin; ULN, Upper limit of normal.
Figure 3. | Box plots showing laboratory results in remdesivir-treated patients and controls. Box plots for the highest ALT, AST, and glucose and lowest hemoglobin for redeliver-treated patients show interquartile range (box), median (line), and whiskers with 5th and 95th percentiles. Outliers are shown with solid circles. Only peak glucose significantly differed between matched remdesivir-treated patients and historical controls.
Although a prior study demonstrated that remdesivir may be associated with bradycardia (25), we found no difference between the rates of bradycardia in remdesivir-treated patients and matched controls. This is reassuring given that patients with eGFR ,30 ml/min per 1.73 m2 are likely to have higher exposure to the active metabolite of remdesivir and are more likely to have cardiovascular disease at baseline. Overall, the high rate of clinical events in the control group reflects the severity of COVID-19 among hospitalized patients as well as the high comorbidity burden and frailty of patients with eGFR ,30 ml/min per 1.73 m2 ; this highlights the importance of benchmarking comparisons against appropriately matched controls
Figure 4. | Creatinine trends among patients who were not on KRT at baseline. Serum creatinine values for each patient throughout the study period are shown on a log2 scale. Patients shown in red had $50% rise in serum creatinine or initiation of KRT. Initiation of KRT in one remdesivir-treated patient is demarcated by a dialysis machine icon.
Prior single-center and multicenter patient series of off-label remdesivir use in patients with ESKD have suggested that it is safe and well tolerated. Our finding that clinically significant transaminase elevations were rare and not increased with remdesivir treatment confirms all prior reports of remdesivir in patients with eGFR ,30 ml/min per 1.73 m2 (26–29). Pettit et al. (27) found no significant increase in adverse events or increases in ALT, AST, or serum creatinine when redeliver was given to patients with eGFR ,30 ml/min per 1.73 m2 compared with patients with eGFR .30 ml/min per 1.73 m2 , and they found that none of the transaminase or creatinine elevations were attributed to remdesivir use. Estiverne et al. (30) found that among 18 patients with eGFR ,30 ml/min per 1.73 m2 who received remdesivir, there were two cases of transaminitis (ALT or AST more than five times the upper limit of normal), both of which were attributed to shock liver. Aiswarya et al. (29) studied 48 patients with ESKD on dialysis treated with remdesivir at a single hospital in India and noted that remdesivir was well tolerated, but one patient experienced acute coronary syndrome after the first dose of remdesivir. Relatedly, our study provides
Two analyses of the World Health Organization pharmacovigilance database have identified that reports of AKI are more commonly reported after remdesivir use compared with other medications used to treat COVID-19 (hydroxycholoroquine, dexamethasone, and tocilizumab) (31,32); however, reporting bias exists in pharmacovigilance databases. Wongboonsin et al. (33) reported a case of worsening kidney function in a redeliver-treated patient with biopsy-proven osmotic tubulopathy, which can occur when the kidney tubules become overwhelmed with an indigestible carbohydrate load, suggesting that there is a risk of nephrotoxicity from the accumulation of the SBECD excipient; this is the only reported case to date in the literature, and this patient also had severe collapsing focal segmental glomerulopathy triggered by COVID-19, suggesting that osmotic tubulopathy is rare (33). Estiverne et al. (30) also reported one patient with worsening kidney function that was possibly attributed to remdesivir. However, it is important to note that this and all prior series have not had historical comparators with COVID-19 who did not receive remdesivir, and it is important to note that COVID-19 is associated with high rates of AKI in hospitalized patients (4,34). In this regard, our comparison of creatinine trends between remdesivir-treated patients and historical controls in this study is reassuring; the vast majority of remdesivir-treated patients had stable to improving serum creatinine (Figure 4). Biancalana et al. (35) evaluated a cohort of 80 elderly patients receiving redeliver and found that many experienced a rise in eGFR during treatment; they speculated that remdesivir might promptly counteract severe acute respiratory syndrome coronavirus 2–mediated injury and attenuate systemic inflammation. Buxeda et al. (36) reported that redeliver was safe in a series of 51 kidney transplant recipients and that early use (within 48 hours of hospitalization) was associated with a trend toward shortened hospital length of stay. reassurance, as there were no cases of cardiac arrest and no increased risk of cardiac arrhythmia in the remdesivir-treated patients compared with historical controls.
Our study had several limitations. This is a single healthcare system, and therefore, this limits generalizability; despite this, our matched cohort was racially and ethnically diverse. Our sample size was small, and we were only able to find appropriate matches for 31 of the 34 remdesivir-treated patients; even so, there were still differences between the matched groups. We chose historical controls from the first wave (prior to remdesivir's EUA) because selecting controls who did not receive remdesivir after EUA would have introduced significant indication bias; however, the rapidly changing standard of care during the pandemic, including use of corticosteroids and changes in supportive care, makes it challenging to identify appropriate controls. A much larger study will be needed to have a robust estimate of safety. However, this study is among the largest series of off-label use in this population. Our study is also limited by the retrospective ascertainment of clinical outcomes and the fact that investigators were not blinded to treatment assignment. The fact that safety outcomes were predefined and that every physician and nursing note was reviewed by two investigators minimizes this bias.
Acute kidney disease and CKD are among the most important risk factors for adverse outcomes in patients with COVID-19. The exclusion of patients with kidney disease from clinical trials of lifesaving therapies is an important problem that the COVID-19 pandemic has highlighted (37,38). Although conclusive data on the safety of remdesivir among individuals with eGFR ,30 ml/min per 1.73 m2 are lacking, our report adds to a growing body of data suggesting that a short course of remdesivir may be safe in patients with AKI, advanced CKD, and ESKD. Definitive safety and efficacy data will follow from the Study to Evaluate the Efficacy and Safety of Remdesivir in Participants with Severely Reduced Kidney Function Who Are Hospitalized for Coronavirus Disease 2019, a randomized, controlled trial recruiting patients with severe COVID-19 who have eGFR ,30 ml/min per 1.73 m2 (39).
Disclosures
M.E. Sise reports consultancy agreements with Bioporto; research funding from Abbvie, EMD-Serono, Gilead Sciences, and Merck; honoraria from the International Society of Hemodialysis for the Hemodialysis University Lecture; and scientific advisor or membership with Gilead Sciences as a scientific advisory board member and Travere Therapeutics as a scientific advisory board member. All remaining authors have nothing to disclose. Funding This work was funded by a Gilead Sciences (Gilead) investigator-initiated grant to Massachusetts General Hospital (to M.E. Sise). Acknowledgments All aspects of the study (protocol, data capture, analysis, and manuscript preparation) were performed by M.E. Sise and her coinvestigators at Massachusetts General Hospital. Author Contributions M.E. Sise conceptualized the study; J.D. Long, R. Seethapathy, M.E. Sise, I.A. Strohbehn, and S. Zhao were responsible for data curation; R. Seethapathy and M.E. Sise were responsible for investigation; M.E. Sise and S. Zhao were responsible for formal analysis; M.E. Sise was responsible for methodology; M.E. Sise was responsible for project administration; M.E. Sise and I.A.
Strohbehn were responsible for resources; I.A. Strohbehn was responsible for software; M.E. Sise was responsible for validation; M.E. Sise was responsible for visualization; M.E. Sise was responsible for funding acquisition; M.E. Sise provided supervision; R. Seethapathy and M.E. Sise wrote the original draft; and J.D. Long, R. Seethapathy, M.E. Sise, I.A. Strohbehn, and S. Zhao reviewed and edited the manuscript.
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