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Remdesivir Use and Hospital Length of Stay—The Paradox of a Clinical Trial vs Real-Life Use

Remdesivir Use and Hospital Length of Stay—The Paradox of a Clinical Trial vs Real-Life Use Invited Commentary | Infectious Diseases Remdesivir Use and Hospital Length of Stay—The Paradox of a Clinical Trial vs Real-Life Use Gio J. Baracco, MD Remdesivir is the only antiviral drug approved by the Food and Drug Administration (FDA) for the Related article 1,2 treatment of COVID-19. It received its FDA Emergency Use Authorization (EUA) in May 2020 and Author affiliations and article information are its full approval in October 2020, largely on the heels of the ACTT-1 trial. The primary outcome of this listed at the end of this article. placebo-controlled randomized clinical trial was time to recovery, defined as how many days it took for the patient to either be discharged from the hospital or stay in the hospital but not require oxygen 3 3 or ongoing medical care (ie, for infection control purposes only). The ACTT-1 trial showed that patients receiving remdesivir recovered after a median of 10 days, compared with 15 days for the placebo group. There was also a numerical but not a statistically significant difference in mortality between groups. The study by Ohl et al looked at the real-world outcomes associated with using remdesivir under this EUA in a large cohort of patients hospitalized with COVID-19 at the nation’s largest integrated health care network, the Department of Veteran Affairs (VA). Like the ACTT-1 trial, they did not find a mortality difference but unlike it, Ohl et al found that the use of remdesivir was associated with increased length of stay, rather than decreased it. Why? The simplest explanation would be that there is a significant selection bias: that patients receiving remdesivir in practice are likely to be more severely ill than those not receiving it and therefore likely to stay hospitalized longer. While that is always a possibility in retrospective cohort studies, Ohl et al were exhaustive in their selection of propensity score–matched patients, using demographic, comorbidity, illness severity, concomitant medications, and time-dependent covariates to obtain a comparable cohort. Every facility had equal access to remdesivir via a centralized distribution system, and facilities had to certify inclusion and exclusion criteria prior to getting the drug delivered to them. The most likely explanation could be that patients were kept in the hospital longer than necessary to complete the 5-day or 10-day prescribed course of remdesivir. To understand why this may have happened, context is important. During the study period, remdesivir was under an EUA. Patients had to meet inclusion and exclusion criteria, give verbal consent, and be monitored for adverse events, including infusion reactions and daily renal and liver function laboratory tests. In addition, there was little else, other than dexamethasone, to offer patients who, by definition, had severe forms of COVID-19, and the management of COVID-19 was a new and continuously evolving field with a huge emotional component. While the protocol of the ACTT-1 trial called for the remdesivir infusions to be stopped early if the patient met the primary outcome of the study and was ready to be discharged, this detail was not adequately translated to the clinicians treating these patients. The FDA EUA fact sheet for health care practitioners and the VA Pharmacy Benefits Management’s instructions for its clinicians only referred to a 5-day or a 10-day course recommendation but did not include explicit language about early 2,5 termination for recovered patients. Additionally, VA facilities were sent 10-day courses of therapy for each of their patients who met the criteria. The study by Ohl et al has several limitations, particularly those associated with the retrospective nature of the study. In this study, the median length of stay for remdesivir recipients was 6 days, compared with 3 days for the matched patients who did not receive remdesivir. This is in stark contrast to the patients in the ACTT-1 study, who achieved the primary outcome after 10 days Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(7):e2116057. doi:10.1001/jamanetworkopen.2021.16057 (Reprinted) July 15, 2021 1/3 JAMA Network Open | Infectious Diseases Remdesivir Use and Hospital Length of Stay compared with 15 days in the control group. Clearly, the groups in both studies were different and/or treated differently. Were the patients enrolled in ACTT-1 more severely ill? Were there other factors preventing early discharge, such as infection control discontinuation policies? Were clinicians less comfortable with early discharge of patients with COVID-19? Does the VA provide closer postdischarge monitoring than sites that enrolled patients in ACTT-1, allowing for early discharge? Regardless of the reason, it is evident from the study by Ohl et al that using remdesivir was associated with delaying the discharge of patients with COVID-19. However, approximately half of patients who received remdesivir were able to be matched to an appropriate control patient, and they generally had less severe illness than patients who were not matched with controls. Since most patients with severe COVID-19 received remdesivir, finding more suitable controls was not possible. Had patients who were more severely ill and their propensity score–match controls with more severe illness been included, the association of remdesivir with length of stay might have been diluted. In medicine, we often prescribe medication on the promise of a statistical chance of some positive outcome. Most patients who receive the medication do well (or they do not), but at the individual level it is often difficult to know whether the outcome is related to the administration of the medication in question. Were they going to get better regardless? Were they going to have an adverse outcome regardless? Examples include oseltamivir for influenza, or antiplatelet drugs or cholesterol-lowering medication for cardiovascular disease. Sometimes the potential benefits are significant, and sometimes they are marginal. These potential benefits are usually weighed against the burden of administering the medication in terms of cost, adverse events, or need for monitoring. The real-life application of a drug promising to hasten discharge from the hospital as its primary beneficial outcome must include an assessment of how easy it is to do so and make it clear that once a patient reaches that point, they can discontinue the drug. The paradoxical findings in the study by Ohl et al compared with the study used for its authorization illustrate this point very clearly. ARTICLE INFORMATION Published: July 15, 2021. doi:10.1001/jamanetworkopen.2021.16057 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Baracco GJ. JAMA Network Open. Corresponding Author: Gio J. Baracco MD, Hospital Epidemiology and Occupational Health Service, Miami VA Healthcare System, 1201 NW 16th St, Ste B1238, Miami, FL 33125 (gbaracco@med.miami.edu). Author Affiliations: Division of Infectious Diseases, Miller School of Medicine, University of Miami, Miami, Florida; Hospital Epidemiology and Occupational Health Service, Miami VA Healthcare System, Miami, Florida. Conflict of Interest Disclosures: Dr Baracco reported receiving salary support from the US Department of Veterans Affairs. Disclaimer: The statements contained in this article reflect the views of the author and do not represent the official positions of the US Department of Veterans Affairs, the US government, or other author affiliate organizations. REFERENCES 1. U.S. Food and Drug Administration. FDA’s approval of Veklury (remdesivir) for the treatment of COVID-19—the science of safety and effectiveness. Accessed May 24, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/ fdas-approval-veklury-remdesivir-treatment-covid-19-science-safety-and-effectiveness 2. VA Pharmacy Benefits Management Services. Remdesivir emergency use authorization (EUA) requirements: May 2020. Accessed May 24, 2021. https://www.va.gov/covidtraining/docs/20200618_Dynamic_Drugs_in_the_ Battle_of_COVID_19/Remdesivir_Emergency_Use_Authorization_Requirements.pdf 3. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764 4. Ohl ME, Miller DR, Lund BC, et al. Association of remdesivir treatment with survival and length of hospital stay among US veterans hospitalized with COVID-19. JAMA Netw Open. 2021;4(7):e2114741. doi:10.1001/ jamanetworkopen.2021.14741 JAMA Network Open. 2021;4(7):e2116057. doi:10.1001/jamanetworkopen.2021.16057 (Reprinted) July 15, 2021 2/3 JAMA Network Open | Infectious Diseases Remdesivir Use and Hospital Length of Stay 5. US Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Accessed May 24, 2021. https://www.fda.gov/media/ 137566/download JAMA Network Open. 2021;4(7):e2116057. doi:10.1001/jamanetworkopen.2021.16057 (Reprinted) July 15, 2021 3/3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Remdesivir Use and Hospital Length of Stay—The Paradox of a Clinical Trial vs Real-Life Use

JAMA Network Open , Volume 4 (7) – Jul 15, 2021

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Abstract

Invited Commentary | Infectious Diseases Remdesivir Use and Hospital Length of Stay—The Paradox of a Clinical Trial vs Real-Life Use Gio J. Baracco, MD Remdesivir is the only antiviral drug approved by the Food and Drug Administration (FDA) for the Related article 1,2 treatment of COVID-19. It received its FDA Emergency Use Authorization (EUA) in May 2020 and Author affiliations and article information are its full approval in October 2020, largely on the heels of the ACTT-1 trial. The primary outcome of this listed at the end of this article. placebo-controlled randomized clinical trial was time to recovery, defined as how many days it took for the patient to either be discharged from the hospital or stay in the hospital but not require oxygen 3 3 or ongoing medical care (ie, for infection control purposes only). The ACTT-1 trial showed that patients receiving remdesivir recovered after a median of 10 days, compared with 15 days for the placebo group. There was also a numerical but not a statistically significant difference in mortality between groups. The study by Ohl et al looked at the real-world outcomes associated with using remdesivir under this EUA in a large cohort of patients hospitalized with COVID-19 at the nation’s largest integrated health care network, the Department of Veteran Affairs (VA). Like the ACTT-1 trial, they did not find a mortality difference but unlike it, Ohl et al found that the use of remdesivir was associated with increased length of stay, rather than decreased it. Why? The simplest explanation would be that there is a significant selection bias: that patients receiving remdesivir in practice are likely to be more severely ill than those not receiving it and therefore likely to stay hospitalized longer. While that is always a possibility in retrospective cohort studies, Ohl et al were exhaustive in their selection of propensity score–matched patients, using demographic, comorbidity, illness severity, concomitant medications, and time-dependent covariates to obtain a comparable cohort. Every facility had equal access to remdesivir via a centralized distribution system, and facilities had to certify inclusion and exclusion criteria prior to getting the drug delivered to them. The most likely explanation could be that patients were kept in the hospital longer than necessary to complete the 5-day or 10-day prescribed course of remdesivir. To understand why this may have happened, context is important. During the study period, remdesivir was under an EUA. Patients had to meet inclusion and exclusion criteria, give verbal consent, and be monitored for adverse events, including infusion reactions and daily renal and liver function laboratory tests. In addition, there was little else, other than dexamethasone, to offer patients who, by definition, had severe forms of COVID-19, and the management of COVID-19 was a new and continuously evolving field with a huge emotional component. While the protocol of the ACTT-1 trial called for the remdesivir infusions to be stopped early if the patient met the primary outcome of the study and was ready to be discharged, this detail was not adequately translated to the clinicians treating these patients. The FDA EUA fact sheet for health care practitioners and the VA Pharmacy Benefits Management’s instructions for its clinicians only referred to a 5-day or a 10-day course recommendation but did not include explicit language about early 2,5 termination for recovered patients. Additionally, VA facilities were sent 10-day courses of therapy for each of their patients who met the criteria. The study by Ohl et al has several limitations, particularly those associated with the retrospective nature of the study. In this study, the median length of stay for remdesivir recipients was 6 days, compared with 3 days for the matched patients who did not receive remdesivir. This is in stark contrast to the patients in the ACTT-1 study, who achieved the primary outcome after 10 days Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(7):e2116057. doi:10.1001/jamanetworkopen.2021.16057 (Reprinted) July 15, 2021 1/3 JAMA Network Open | Infectious Diseases Remdesivir Use and Hospital Length of Stay compared with 15 days in the control group. Clearly, the groups in both studies were different and/or treated differently. Were the patients enrolled in ACTT-1 more severely ill? Were there other factors preventing early discharge, such as infection control discontinuation policies? Were clinicians less comfortable with early discharge of patients with COVID-19? Does the VA provide closer postdischarge monitoring than sites that enrolled patients in ACTT-1, allowing for early discharge? Regardless of the reason, it is evident from the study by Ohl et al that using remdesivir was associated with delaying the discharge of patients with COVID-19. However, approximately half of patients who received remdesivir were able to be matched to an appropriate control patient, and they generally had less severe illness than patients who were not matched with controls. Since most patients with severe COVID-19 received remdesivir, finding more suitable controls was not possible. Had patients who were more severely ill and their propensity score–match controls with more severe illness been included, the association of remdesivir with length of stay might have been diluted. In medicine, we often prescribe medication on the promise of a statistical chance of some positive outcome. Most patients who receive the medication do well (or they do not), but at the individual level it is often difficult to know whether the outcome is related to the administration of the medication in question. Were they going to get better regardless? Were they going to have an adverse outcome regardless? Examples include oseltamivir for influenza, or antiplatelet drugs or cholesterol-lowering medication for cardiovascular disease. Sometimes the potential benefits are significant, and sometimes they are marginal. These potential benefits are usually weighed against the burden of administering the medication in terms of cost, adverse events, or need for monitoring. The real-life application of a drug promising to hasten discharge from the hospital as its primary beneficial outcome must include an assessment of how easy it is to do so and make it clear that once a patient reaches that point, they can discontinue the drug. The paradoxical findings in the study by Ohl et al compared with the study used for its authorization illustrate this point very clearly. ARTICLE INFORMATION Published: July 15, 2021. doi:10.1001/jamanetworkopen.2021.16057 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Baracco GJ. JAMA Network Open. Corresponding Author: Gio J. Baracco MD, Hospital Epidemiology and Occupational Health Service, Miami VA Healthcare System, 1201 NW 16th St, Ste B1238, Miami, FL 33125 (gbaracco@med.miami.edu). Author Affiliations: Division of Infectious Diseases, Miller School of Medicine, University of Miami, Miami, Florida; Hospital Epidemiology and Occupational Health Service, Miami VA Healthcare System, Miami, Florida. Conflict of Interest Disclosures: Dr Baracco reported receiving salary support from the US Department of Veterans Affairs. Disclaimer: The statements contained in this article reflect the views of the author and do not represent the official positions of the US Department of Veterans Affairs, the US government, or other author affiliate organizations. REFERENCES 1. U.S. Food and Drug Administration. FDA’s approval of Veklury (remdesivir) for the treatment of COVID-19—the science of safety and effectiveness. Accessed May 24, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/ fdas-approval-veklury-remdesivir-treatment-covid-19-science-safety-and-effectiveness 2. VA Pharmacy Benefits Management Services. Remdesivir emergency use authorization (EUA) requirements: May 2020. Accessed May 24, 2021. https://www.va.gov/covidtraining/docs/20200618_Dynamic_Drugs_in_the_ Battle_of_COVID_19/Remdesivir_Emergency_Use_Authorization_Requirements.pdf 3. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764 4. Ohl ME, Miller DR, Lund BC, et al. Association of remdesivir treatment with survival and length of hospital stay among US veterans hospitalized with COVID-19. JAMA Netw Open. 2021;4(7):e2114741. doi:10.1001/ jamanetworkopen.2021.14741 JAMA Network Open. 2021;4(7):e2116057. doi:10.1001/jamanetworkopen.2021.16057 (Reprinted) July 15, 2021 2/3 JAMA Network Open | Infectious Diseases Remdesivir Use and Hospital Length of Stay 5. US Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. Accessed May 24, 2021. https://www.fda.gov/media/ 137566/download JAMA Network Open. 2021;4(7):e2116057. doi:10.1001/jamanetworkopen.2021.16057 (Reprinted) July 15, 2021 3/3

Journal

JAMA Network OpenAmerican Medical Association

Published: Jul 15, 2021

References