Hiddo J L Heerspink1,2, Remo H M Furtado3,4, Otavio Berwanger3, Gary G Koch5, Felipe Martinez6, Omar Mukhtar7, Subodh Verma8,9, Samvel B Gasparyan10, Fengming Tang11, Sheryl L Windsor11, Vicente Cés de Souza-Dantas12, Mildren Del Sueldo13, Robert Frankel14, Ali Javaheri15, Rafael A Maldonado16, Caryn Morse17, Marco Mota-Gomes18, Douglas Shemin19, Osvaldo Lourenço Silva20, Alexandre Pereira Tognon3, Marcel Twahirwa21, Joan Buenconsejo22, Russell Esterline22, Jan Oscarsson10, Philip Ambery10, Anna Maria Langkilde10, Mikhail N Kosiborod2,11,23. 1. University of Groningen, University Medical Center Groningen, Groningen, The Netherlands h.j.lambers.heerspink@umcg.nl. 2. The George Institute for Global Health, Newtown, NSW, Australia. 3. Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil. 4. Instituto do Coracao do Hospital das Clinicas da FMUSP, São Paulo, Brazil. 5. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 6. National University of Córdoba, Córdoba, Argentina. 7. Department of Medicine, Experimental Medicine and Immunotherapeutics Division, University of Cambridge, Cambridge, United Kingdom. 8. Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. 9. Department of Surgery and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. 10. Late-stage Development, CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 11. Saint Luke's Mid America Heart Institute, Kansas City, Missouri. 12. Intensive Care Unit, University Hospital Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 13. Department of Cardiology, Clinica de Especialidades, Villa Maria, Argentina. 14. Cardiology, Maimonides Medical Center, New York, New York. 15. Washington University School of Medicine, St Louis, Missouri. 16. Nephrology and Transplantation Service, Clínica Privada Vélez Sarsfield, Postgraduate School of Nephrology, National University of Córdoba, Córdoba, Argentina. 17. Wake Forest School of Medicine, Winston-Salem, North Carolina. 18. Centro Universitário Cesmac/Hospital do Coração de Alagoas, Maceió, Brazil. 19. Division of Kidney Diseases and Hypertension, Alpert Medical School of Brown University, Providence, Rhode Island. 20. Centro Integrado de Pesquisas, Hospital de Base-São José do Rio Preto, São José do Rio Preto, Brazil. 21. Diabetes and Endocrinology Institute, Doctors Hospital at Renaissance, Edinburg, Texas. 22. Late-stage Development, CVRM, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland. 23. School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.
Abstract
BACKGROUND AND OBJECTIVES: Patients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The DARE-19 trial randomized 1250 patients who were hospitalized (231 [18%] had eGFR <60 ml/min per 1.73 m2) with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. Dual primary outcomes (time to new or worsened organ dysfunction or death, and a hierarchical composite end point of recovery [change in clinical status by day 30]), and the key secondary kidney outcome (composite of AKI, KRT, or death), and safety were assessed in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2. RESULTS: The effect of dapagliflozin versus placebo on the primary prevention outcome (hazard ratio, 0.80; 95% confidence interval, 0.58 to 1.10), primary recovery outcome (win ratio, 1.09; 95% confidence interval, 0.97 to 1.22), and the composite kidney outcome (hazard ratio, 0.74; 95% confidence interval, 0.50 to 1.07) were consistent across eGFR subgroups (P for interaction: 0.98, 0.67, and 0.44, respectively). The effects of dapagliflozin on AKI were also similar in participants with eGFR <60 ml/min per 1.73 m2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m2 (hazard ratio, 0.69; 95% confidence interval, 0.37 to 1.29). Dapagliflozin was well tolerated in participants with eGFR <60 and ≥60 ml/min per 1.73 m2. CONCLUSIONS: The effects of dapagliflozin on primary and secondary outcomes in hospitalized participants with COVID-19 were consistent in those with eGFR below/above 60 ml/min per 1.73 m2. Dapagliflozin was well tolerated and did not increase the risk of AKI in participants with eGFR below or above 60 ml/min per 1.73 m2.
BACKGROUND AND OBJECTIVES: Patients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The DARE-19 trial randomized 1250 patients who were hospitalized (231 [18%] had eGFR <60 ml/min per 1.73 m2) with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. Dual primary outcomes (time to new or worsened organ dysfunction or death, and a hierarchical composite end point of recovery [change in clinical status by day 30]), and the key secondary kidney outcome (composite of AKI, KRT, or death), and safety were assessed in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2. RESULTS: The effect of dapagliflozin versus placebo on the primary prevention outcome (hazard ratio, 0.80; 95% confidence interval, 0.58 to 1.10), primary recovery outcome (win ratio, 1.09; 95% confidence interval, 0.97 to 1.22), and the composite kidney outcome (hazard ratio, 0.74; 95% confidence interval, 0.50 to 1.07) were consistent across eGFR subgroups (P for interaction: 0.98, 0.67, and 0.44, respectively). The effects of dapagliflozin on AKI were also similar in participants with eGFR <60 ml/min per 1.73 m2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m2 (hazard ratio, 0.69; 95% confidence interval, 0.37 to 1.29). Dapagliflozin was well tolerated in participants with eGFR <60 and ≥60 ml/min per 1.73 m2. CONCLUSIONS: The effects of dapagliflozin on primary and secondary outcomes in hospitalized participants with COVID-19 were consistent in those with eGFR below/above 60 ml/min per 1.73 m2. Dapagliflozin was well tolerated and did not increase the risk of AKI in participants with eGFR below or above 60 ml/min per 1.73 m2.
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