Acute and chronic kidney disease are important risk factors for hospitalization and death from coronavirus disease 2019 (COVID-19).1Flythe J.E. Assimon M.M. Tugman M.J. Chang E.H. Gupta S. Shah J. Sosa M.A. Renaghan A.D. Melamed M.L. Wilson F.P. Neyra J.A. Rashidi A. Boyle S.M. Anand S. Christov M. Thomas L.F. Edmonston D. Leaf D.E. Investigators S.-C. Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States.Am J Kidney Dis. 2021; 77 (e1. Epub 20200919) (PubMed PMID: 32961244; PMCID: PMC7501875): 190-203https://doi.org/10.1053/j.ajkd.2020.09.003Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar In addition to acute complications of COVID-19, survivors may suffer from a wide range of persistent symptoms collectively referred to as "long COVID", and are at an increased risk of cardiovascular and kidney post-acute sequelae, including myocardial infarction, heart failure, thromboembolic disease, and kidney failure.2Xie Y. Xu E. Bowe B. Al-Aly Z. Long-term cardiovascular outcomes of COVID-19.Nat Med. 2022; 28 (Epub 20220207) (PubMed PMID: 35132265; PMCID: PMC8938267): 583-590https://doi.org/10.1038/s41591-022-01689-3Crossref PubMed Scopus (906) Google Scholar,3Bowe B. Xie Y. Xu E. Al-Aly Z. Kidney Outcomes in Long COVID.Journal of the American Society of Nephrology : JASN. 2021; 32 (Epub 20210901) (PubMed PMID: 34470828; PMCID: PMC8806085): 2851-2862https://doi.org/10.1681/ASN.2021060734Crossref PubMed Scopus (163) Google Scholar It is important to understand whether treatments approved to treat COVID-19 can mitigate the morbidity and mortality of long COVID in high-risk populations. Remdesivir was the first antiviral therapy approved for treatment of COVID-19; a recent meta-analysis of randomized clinical trial data showed that remdesivir reduced mortality in patients hospitalized with COVID-19 who did not require mechanical ventilation (adjusted odds ratio of 0.80 (95% confidence interval [CI] 0.70–0.93]).4Amstutz A, Speich B, Mentré F, Rueegg CS, Belhadi D, Assoumou L, Burdet C, Murthy S, Dodd LE, Wang Y, Tikkinen KAO, Ader F, Hites M, Bouscambert M, Trabaud MA, Fralick M, Lee TC, Pinto R, Barratt-Due A, Lund-Johansen F, Müller F, Nevalainen OPO, Cao B, Bonnett T, Griessbach A, Taji Heravi A, Schönenberger C, Janiaud P, Werlen L, Aghlmandi S, Schandelmaier S, Yazdanpanah Y, Costagliola D, Olsen IC, Briel M. Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials. The Lancet Respiratory Medicine. doi: 10.1016/S2213-2600(22)00528-8.Google Scholar Patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 were excluded from the initial registrational trials of remdesivir, however the FDA label expanded to include all levels of kidney function in July 2023. To determine if the use of remdesivir is associated with differences in long-term cardiovascular and kidney outcomes among patients with reduced eGFR, we designed a propensity-score matched study to compare the risk of major adverse cardiovascular events (MACE) or kidney disease (MAKE) and decline in eGFR among hospitalized patients who received remdesivir versus historical comparators with COVID-19 (Item S1). There were 200 individuals with admission eGFR <60 mL/min/1.73m2 or kidney failure receiving treated with kidney replacement therapy who received remdesivir within 72 hours of admission, and 555 potential historical comparators who met inclusion criteria (Figure 1). A sufficiently close match was found for 198 of the 200 (99%) remdesivir-treated patients, who were variably matched to 335 historical comparators. Among the matched cohorts, 162 (81.8%) remdesivir-treated and 250 (74.6%) historical comparators survived >30 days; pairs with both a matched remdesivir-treated patient and at least one historical comparator who survived > 30 days (148 remdesivir-treated patients and 209 historical controls) are considered as the primary cohort for analysis (Table S1). The mean age was 71 (SD 13), 56.6% were male, and 53.2% were white non-Hispanic, 17.6 % were Black, 16.8% were Hispanic, and 12.3% were Asian. Comorbidities were common; 215 (60.2%) patients had diabetes, 289 (80.9%) patients had hypertension, and 236 (66.1%) had coronary artery disease. The rate of MACE between 30 days and 18 months was high (2.54 events per 100 patient-months), MAKE occurred less commonly (0.74 events per 100 patient-months). There was no significant difference in MACE or MAKE between remdesivir-treated patients and historical comparators followed for 18 months (Figure S1, Table S2). However, remdesivir use was associated with a significant attenuation of eGFR decline between 30 days to 18 months among survivors without kidney failure at baseline (-2.11mL/min/year [95% CI -4.12 to -0.10] vs. -6.45 mL/min/year decline [95% CI -7.97 to -4.93] in historical comparators) (Table 1). Sensitivity analysis using all surviving patients demonstrated similar attenuation of eGFR decline in remdesivir-treated patients compared to historical comparators.Table 1Slope of eGFR decline from 30 days to 18 monthsUnadjusted eGFR slope (95%CI)P value*Adjusted eGFR slope (95% CI)p value*(mL/min/1.73m2 per year decline)(mL/min/1.73m2 per year decline)Paired patients without kidney failure who survived ≥30 days (n=336)Comparators-6.52 (-8.05 to -5.00)-6.45 (-7.97 to -4.93)Remdesivir-2.10 (-4.12 to -0.08)<0.001-2.11 (-4.12 to -0.10)<0.001All patients without kidney failure who survived ≥30 days (n=384)Comparators-6.07 (-7.42 to -4.73)-6.02 (-7.36 to -4.68)Remdesivir-3.60 (-5.39 to -1.82)0.03-3.63 (-5.41 to -1.86)0.04The analysis of eGFR slope includes the 336 patients without baseline kidney failure where at least one matched paired patient survived >30 days. The median and interquartile range (IQR) of number of eGFR per person in follow-up is 7 [IQR: 3, 19], the median time between eGFR measurements is 38 [IQR: 16, 121] days. Sensitivity analysis of all the 384 patients who did not have kidney failure at baseline and survived >30 days revealed similar findings. The multivariable linear mixed-effects models are adjusted for age, sex, black race, diabetes, hypertension, coronary artery disease, congestive heart failure, solid organ transplant, requiring mechanical ventilation within 72 hours, SOFA score, admission serum creatinine, frequency of overall and inpatient encounters in the year prior to admission for COVID-19. *Comparing eGFR slopes between remdesivir-treated patients and historical comparators.Abbreviations: eGFR = estimated glomerular filtration rate, CI = confidence interval, SOFA = sequential organ failure assessment. Open table in a new tab The analysis of eGFR slope includes the 336 patients without baseline kidney failure where at least one matched paired patient survived >30 days. The median and interquartile range (IQR) of number of eGFR per person in follow-up is 7 [IQR: 3, 19], the median time between eGFR measurements is 38 [IQR: 16, 121] days. Sensitivity analysis of all the 384 patients who did not have kidney failure at baseline and survived >30 days revealed similar findings. The multivariable linear mixed-effects models are adjusted for age, sex, black race, diabetes, hypertension, coronary artery disease, congestive heart failure, solid organ transplant, requiring mechanical ventilation within 72 hours, SOFA score, admission serum creatinine, frequency of overall and inpatient encounters in the year prior to admission for COVID-19. *Comparing eGFR slopes between remdesivir-treated patients and historical comparators. Abbreviations: eGFR = estimated glomerular filtration rate, CI = confidence interval, SOFA = sequential organ failure assessment. Our study is in line with prior studies showing that the rate of MACE is high in patients with COVID-19. Bowe et al. found that compared to control groups without COVID-19, patients who survived COVID-19 exhibited an increased burden of cardiovascular conditions, and that repeat episodes of COVID-19 contribute to the burden of long COVID.2Xie Y. Xu E. Bowe B. Al-Aly Z. Long-term cardiovascular outcomes of COVID-19.Nat Med. 2022; 28 (Epub 20220207) (PubMed PMID: 35132265; PMCID: PMC8938267): 583-590https://doi.org/10.1038/s41591-022-01689-3Crossref PubMed Scopus (906) Google Scholar, 5Bowe B. Xie Y. Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection.Nat Med. 2022; 28 (Epub 20221110) (PubMed PMID: 36357676; PMCID: PMC9671810): 2398-2405https://doi.org/10.1038/s41591-022-02051-3Crossref PubMed Scopus (231) Google Scholar Additionally, adverse kidney outcomes are more common in patients with COVID-19; 30-day survivors of COVID-19 exhibited higher risk of acute kidney injury, 50% eGFR decline, and kidney failure.3Bowe B. Xie Y. Xu E. Al-Aly Z. Kidney Outcomes in Long COVID.Journal of the American Society of Nephrology : JASN. 2021; 32 (Epub 20210901) (PubMed PMID: 34470828; PMCID: PMC8806085): 2851-2862https://doi.org/10.1681/ASN.2021060734Crossref PubMed Scopus (163) Google Scholar Furthermore, COVID-19 can trigger collapsing glomerulopathy in patients with high-risk APOL1 genotype and has poor long-term outcomes.6Kudose S. Santoriello D. Bomback A.S. Sekulic M. Batal I. Stokes M.B. Ghavami I.A. Kim J.S. Marasa M. Xu K. Peleg Y. Barasch J. Canetta P. Rasouly H.M. Gharavi A.G. Markowitz G.S. D'Agati V.D. Longitudinal Outcomes of COVID-19-Associated Collapsing Glomerulopathy and Other Podocytopathies.J Am Soc Nephrol. 2021; 32 (Epub 20211020) (PubMed PMID: 34670811; PMCID: PMC8806099): 2958-2969https://doi.org/10.1681/ASN.2021070931Crossref PubMed Scopus (28) Google Scholar Understanding whether treatments for COVID-19 reduce long COVID-19 is an important unmet need. Our study has limitations. First, we chose historical comparators from the first wave of COVID-19 prior to EUA of remdesivir to avoid confounding by indication and minimize selection bias. We performed detailed chart review to ensure accurate information on disease severity and other baseline covariates and achieved good balance between the remdesivir-treated patients and matched untreated comparators after propensity score matching. Given the study period (March-November 2020), treated and untreated patients were exposed to the same variant (wild type), the vast majority were first infections, and all patients were unvaccinated. However, standard of care differed throughout the study period; all historical comparators were admitted prior to routine use of dexamethasone at our center; this may have impacted the long-term outcomes.7Group R.C. Horby P. Lim W.S. Emberson J.R. Mafham M. Bell J.L. Linsell L. Staplin N. Brightling C. Ustianowski A. Elmahi E. Prudon B. Green C. Felton T. Chadwick D. Rege K. Fegan C. Chappell L.C. Faust S.N. Jaki T. Jeffery K. Montgomery A. Rowan K. Juszczak E. Baillie J.K. Haynes R. Landray M.J. Dexamethasone in Hospitalized Patients with Covid-19.N Engl J Med. 2021; 384 (Epub 20200717) (PubMed PMID: 32678530; PMCID: PMC7383595): 693-704https://doi.org/10.1056/NEJMoa2021436Crossref PubMed Scopus (7019) Google Scholar Second, patients may have been hospitalized outside our healthcare network and not captured in "Care Everywhere" documentation. To minimize the risk of bias, we matched patients based on the number of inpatient and total encounters in our healthcare network in the 1 year prior to COVID-19. Finally, our study evaluated patients who received remdesivir at the time of hospital admission, deploying antiviral strategies earlier in the disease course may more effectively reduce the high rates of MACE. Future studies are needed to test whether early antiviral therapies can more effectively decrease the risk of long COVID. In conclusion, use of remdesivir in hospitalized patients with COVID-19 and reduced eGFR not associated with a decreased risk of MACE or MAKE, but was associated with a less steep slope of eGFR decline among survivors followed up to 18 months. Item S1: Supplementary Methods Figure S1: Association between remdesivir use and MACE and MAKE between 30 days and 18 months after hospitalization for COVID-19 Table S1: Patient characteristics pre- and post-propensity score matching Table S2: Association between remdesivir use and adverse cardiovascular and kidney outcomes at multiple timepoints Descriptive Text for Online Delivery Supplementary File (PDF) Item S1, Figure S1, Tables S1–S2 Research idea and study design: MES; data acquisition: JED, QW, DC, RS, JCL, IS, MES; data analysis / interpretation: JED, QW, SZ, MES; supervision: MES. Each author contributed important intellectual content during manuscript drafting and revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This worked was funded through an investigator-initiated grant to MES from Gilead. MES has received research funding from Gilead, Novartis, Cabaletta, Merck, Abbvie, Angion, Otsuka, and EMD-Serono. Dr. Sise has served as a paid consultant for scientific advisory boards for Travere, Calliditas, Novartis, Mallinckrodt, and Vera and as a paid Data Monitoring Committee member for Alpine Immunosciences. A subset of patients included in this analysis of long-term outcomes have been previously reported in published manuscript describing short-term kidney outcomes (PMID 36848366, 35373125). Received September 15, 2023. Evaluated by 1 external peer reviewer, with direct editorial input from the Statistical Editor and the Editor-in-Chief. Accepted in revised form January 26, 2024. The following is/are the supplementary data to this article: Download .pdf (.24 MB) Help with pdf files
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