A Propensity Score–Matched Observational Study Of Remdesivir in Patients With COVID-19 And Severe Kidney Disease
Nov 30, 2023
Abstract
Background Remdesivir is not currently approved for patients with eGFR,30 ml/min per 1.73 m2 . We aimed to determine the safety of remdesivir in patients with kidney failure.
Methods This study was a retrospective cohort study of patients with COVID-19 hospitalized between May 2020 and January 2021 with eGFR,30 ml/min per 1.73 m2 who received remdesivir and historical controls with COVID-19 hospitalized between March 1, 2020, and April 30, 2020 prior to the emergency use authorization of remdesivir within a large health care system. Patients were 1:1 matched by propensity scores accounting for factors associated with treatment assignment. Adverse events and hospital outcomes were recorded by manual chart review.
Results The overall cohort included 34 hospitalized patients who initiated remdesivir within 72 hours of hospital admission with eGFR,30 ml/min per 1.73 m2 and 217 COVID-19 controls with eGFR,30 ml/min per 1.73 m2. The propensity score–matched cohort included 31 remdesivir-treated patients and 31 nonremdesivir-treated controls. The mean age was 74.0 (SD513.8) years, 57% were women, and 68% were white participants. A total of 26% had ESKD. Among patients who were not on dialysis prior to initiating remdesivir, one developed worsening kidney function (defined as $50% increase in creatinine or initiation of KRT) compared with three in the historical control group. There was no increased risk of cardiac arrhythmia, cardiac arrest, altered mental status, or clinically significant anemia or liver function test abnormalities. There was a significantly increased risk of hyperglycemia, which may be partly explained by the increased use of dexamethasone in the remdesivir-treated population.
Conclusions In this propensity score–matched study, redeliver was well tolerated in patients with eGFR,30 ml/min per 1.73 m2 .
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Introduction
There have been over 200 million cases of coronavirus disease 2019 (COVID-19) worldwide as of August 10, 2021 (1). Severe COVID-19 can cause multiorgan injury (2,3), and AKI has emerged as a common complication of COVID-19. In the first wave of the pandemic, multiple studies demonstrated that the rate of AKI among hospitalized patients was between 17% and 37%; however, with improvements in care, the rate of AKI has decreased (4–11). Nevertheless, patients with low eGFR due to either AKI or pre-existing CKD and patients with ESKD have a significantly increased risk of death from COVID-19 (12,13).
Remdesivir is the only antiviral treatment that has been approved for the treatment of COVID-19 in patients with severe COVID-19. However, because of concerns about the drug’s potential toxicity in patients with kidney disease related to both metabolism and elimination of remdesivir and the potential accumulation of its sulfobutylether-b-cyclodextrin (SBECD) excipient, the Food and Drug Administration approval states that remdesivir is not recommended in patients with eGFR ,30 ml/min per 1.73 m2 . Remdesivir is a prodrug that, after it is metabolized to remdesivir triphosphate, acts as an analog of ATP, competing for incorporation by RNA-dependent RNA polymerase and interfering with viral RNA replication. Rare but serious side effects of remdesivir include transaminitis and hypersensitivity/infusion reactions (14).
Given the limited duration of treatment (5 days) and relatively low concentration of SBECD excipient, it has been suggested that the benefits of remdesivir may outweigh risks in select patients with eGFR ,30 ml/min per 1.73 m2 who present early in their disease course when antiviral therapy is most likely to be effective (15). Thus, within our health care network, off-label remdesivir was offered to patients with eGFR ,30 ml/min per 1.73 m2 when infectious diseases experts and nephrologists agreed that these potential benefits outweighed risks. There is a small number of case series of remdesivir use in patients with eGFR ,30 ml/min per 1.73 m2 ; however, no prior series included matched comparators. To address this knowledge gap, we sought to compare the risk of key safety events and hospital outcomes in patients treated with redeliver with propensity score–matched patients who did not receive redeliver during the early phase of the first COVID-19 surge in Boston, Massachusetts when redeliver was not yet available (March 5, 2020 to April 30, 2020).
Materials and Methods
Patient Population and Data Acquisition
We conducted an observational, retrospective cohort study of hospitalized adults with COVID-19 within the Mass General Brigham (MGB) healthcare system located in the Boston region. Inclusion criteria for remdesivir-treated patients were (1) receipt of remdesivir within 72 hours of hospital admission and (2) receipt of KRT or eGFR,30 ml/min per 1.73 m2 on the basis of their creatinine level just prior to the first dose of remdesivir administration. eGFR was calculated via the Chronic Kidney Disease Epidemiology Collaboration equation (16). Patients were excluded if they had begun remdesivir prior to transfer to our health care system from an outside hospital because we could not evaluate baseline laboratory studies in these patients. Potential historical comparators were identified using the MGB Research Patients Data Registry (RPDR) to identify consecutive patients diagnosed with COVID-19 by RT-PCR between March 1, 2020 and April 30, 2020 who were hospitalized for .24 hours and had eGFR ,30 ml/ min per 1.73 m2 within the first 72 hours of admission. We developed inclusion/exclusion criteria a priori to identify candidates who would have qualified for remdesivir had they been admitted after the emergency use authorization (EUA) when remdesivir became available. Inclusion criteria for historical comparators included (1) admission for COVID-19 with oxygen saturation #94% on room air or requiring supplemental oxygen within 72 hours of admission and (2) eGFR ,30 ml/min per 1.73 m2 or receiving KRT within the first 72 hours of admission. Exclusion criteria included (1) evidence of decompensated liver disease within 72 hours of admission, (2) enrollment in a placebo-controlled trial of redeliver, (3) initiation of hospice care prior to receiving COVID–19–directed therapies, or (4) transfer from outside facility.
Patient characteristics, including demographics, laboratory tests, diagnosis, and medications, were obtained from MGB RPDR, which is the central data repository of MGB used for research and quality improvement purposes (17,18). Race/ethnicity was defined by incorporating race data and primary language spoken using an algorithm shown in Supplemental Table 1. Pretreatment creatinine was defined by the serum creatinine value just prior to remdesivir initiation. “Prehospital” baseline creatinine was determined by chart review according to the following algorithm. When available, the closest outpatient creatinine value between 14 and 365 days prior to admission was used; if not available, then the minimum serum creatinine during the hospital stay was used. CKD was defined as a “prehospital” baseline creatinine that corresponded to an eGFR ,60 ml/min per 1.73 m2 . Comorbidities were defined by the presence of at least two diagnoses International Classification of Diseases (ICD) 9/10 codes using the “diagnoses domain” (Supplemental Table 2). Baseline medications were defined by at least one instance of a prescribed medication within 1 year of baseline obtained from the “medications domain” (Supplemental Table 3). Laboratory studies were defined by the worst value within 72 hours of admission. The sequential organ failure assessment (SOFA) score was calculated according to the equation by Vincent et al. (19) using the most severe values obtained prior to remdesivir initiation or within 72 hours from admission for patients and controls, respectively.
A manual chart review was performed by two physicians (R.S. and M.E.S.) who reviewed each physician and nursing note to determine adverse events for all case and control patients. Remdesivir-treated patients were chart-reviewed for their entire remdesivir course plus 48 hours afterward (typically corresponding to 7 days), and control patients were chart-reviewed for the first 7 days of hospitalization. Clinical adverse events of interest were cardiac arrhythmia, cardiac arrest, seizure, and altered mental status. Laboratory adverse events of interest were transaminitis (more than five times the upper limit of normal for aspartase aminotransferase [AST] and alanine aminotransferase [ALT]), worsening kidney function, anemia (hemoglobin,8 g/dl), and hyperglycemia (blood glucose .200 mg/dl). Worsening kidney function was defined as a rise in serum creatinine $50% for all patients who were not on KRT prior to baseline. For remdesivir-treated patients, the pretreatment creatinine was the value just prior to the first administered dose of remdesivir; for control patients, the admission creatinine was used. All adverse events of interest were defined a priori.
Our institutional review board approved the protocol and waived the need for informed consent. The research was conducted in accordance with the Helsinki Declaration.
Statistical Analyses
Baseline characteristics were described using means and SDs or medians and interquartile ranges for continuous variables and frequencies and percentages for categorical variables.
To minimize bias from nonrandomized treatment assignment, remdesivir-treated patients were matched to nonremdesivir-treated controls using a propensity score (PS). PSs were first determined on the basis of a multivariate logistic regression model that estimated the probability of receiving remdesivir. The covariates included in the logistic regression model were age; sex; race/ethnicity; SOFA score; invasive mechanical ventilation within 72 hours after admission; pretreatment/admission creatinine level; and history of hypertension, diabetes mellitus, ESKD, and prior solid organ transplantation. For patients with ESKD, the admission creatinine level was imputed as 10 mg/dl because the creatinine values for these patients are modified by dialysis. We then matched the remdesivir-treated patients and nonremdesivir-treated controls using 1:1 nearest neighbor greedy matching without replacement and a caliper of 0.1 SD of the PS. Standardized differences were calculated for the patients and controls before and after matching (20,21).
Following PS matching, patient outcomes were examined using the McNemar test for binary outcomes (proportion experiencing clinical adverse events, 28-day all-cause mortality) and paired t-test or Wilcoxon signed rank test for continuous outcomes (lowest hemoglobin and highest AST, ALT, and blood glucose), as appropriate. Statistical analyses were performed using SAS Version 16. All P values were two-sided, and P50.05 was considered statistically significant.
Figure 1. | Patient flow and exclusions. COVID-19, coronavirus disease 2019; EUA, emergency use authorization; O2, oxygen.
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