Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice PointsFREE
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Abstract
Background:
Remdesivir is approved for the treatment of adults hospitalized with COVID-19.
Purpose:
To update a living review of remdesivir for adults with COVID-19.
Data Sources:
Several electronic U.S. Food and Drug Administration, company, and journal websites from 1 January 2020 through 19 October 2021.
Study Selection:
English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19.
Data Extraction:
One reviewer abstracted, and a second reviewer verified data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used.
Data Synthesis:
Since the last update (search date 9 August 2021), 1 new RCT and 1 new subtrial comparing a 10-day course of remdesivir with control (placebo or standard care) were identified. This review summarizes and updates the evidence on the cumulative 5 RCTs and 2 subtrials for this comparison. Our updated results confirm a 10-day course of remdesivir, compared with control, probably results in little to no mortality reduction (5 RCTs). Updated results also confirm that remdesivir probably results in a moderate increase in the proportion of patients recovered by day 29 (4 RCTs) and may reduce time to clinical improvement (2 RCTs) and hospital length of stay (4 RCTs). New RCTs, by increasing the strength of evidence, lead to an updated conclusion that remdesivir probably results in a small reduction in the proportion of patients receiving ventilation or extracorporeal membrane oxygenation at specific follow-up times (4 RCTs). New RCTs also alter the conclusions for harms—remdesivir, compared with control, may lead to a small reduction in serious adverse events but may lead to a small increase in any adverse event.
Limitation:
The RCTs differed in definitions of COVID-19 severity and outcomes reported.
Conclusion:
In hospitalized adults with COVID-19, the findings confirm that remdesivir probably results in little to no difference in mortality and increases the proportion of patients recovered. Remdesivir may reduce time to clinical improvement and may lead to small reductions in serious adverse events but may result in a small increase in any adverse event.
Primary Funding Source:
U.S. Department of Veterans Affairs.
This is the fifth update of our living, rapid review on remdesivir for adults with COVID-19 (1). Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA (2), is approved by the U.S. Food and Drug Administration for the treatment of adults hospitalized with COVID-19 (3). Our first update, which included randomized controlled trials (RCTs) published through 7 December 2020 (4–8), led to a major update (9). Our second update, including RCTs published through 8 February 2021, found no new evidence (10). Our third update (11) derived from RCTs published through 10 May 2021 included 1 new RCT (12), and our fourth update of RCTs published through 9 August 2021 (13) included 1 new add-on subtrial of the World Health Organization (WHO) Solidarity trial—the Norwegian Solidarity trial (14). On the basis of the results from these RCTs, we had previously concluded that a 10-day course of remdesivir probably results in little to no difference in mortality but probably reduces serious adverse events and may reduce time to recovery in hospitalized patients. Two RCTs found that a 10-day course was not more effective than a 5-day course for moderate and severe disease (6, 7).
This fifth quarterly update including RCTs published through 19 October 2021 is the final update for this living review according to the preplanned protocol. It summarizes information on remdesivir from 2 newly published RCTs by Ader and colleagues (DisCoVeRy [Trial of Treatments for COVID-19 in Hospitalized Adults]; subtrial) (15) and Abd-Elsalam and colleagues (16) alongside previous updates. We update previous analyses and certainty of evidence (COE) and conduct cumulative meta-analyses, where feasible. In addition, we report on results of SARS-CoV-2 clearance.
Methods
We included RCTs evaluating remdesivir for adults with COVID-19 using methods identical to those described previously (1, 9). Our literature search was updated to include RCTs published through 19 October 2021 and used the original search strategies and inclusion criteria (Supplement Table 1). DisCoVeRy (15) is a subtrial of Solidarity. Results on some patients were also included in the published Solidarity report (8). Hence, for outcomes that were reported by both DisCoVeRy and Solidarity (mortality and new need for ventilation), we did not include DisCoVeRy data in our main analyses to avoid double counting persons. The DisCoVeRy authors provided us data for DisCoVeRy participants who were not previously included in published Solidarity results for these end points (Mentré F. Personal communication.). We used these unpublished data to conduct sensitivity analyses. For outcomes not reported in Solidarity (proportion recovered, proportion on ventilation at follow-up, and adverse events), we included data of all DisCoVeRy patients in our main analyses. Tools to assess risk of bias (17) and estimate COE (18) were unchanged (Supplement Tables 2 and 9). The definitions of our a priori–defined outcomes, both critical (mortality, proportion recovered, hospital length of stay, and serious adverse events) and important (time to clinical improvement, need for ventilation or extracorporeal membrane oxygenation [ECMO], and any adverse event) and our a priori–established thresholds for estimating effect magnitude for these outcomes were also unchanged (Appendix Table, footnote;) (1).
Data Synthesis and Analysis
We conducted a cumulative meta-analysis combining data from previous updates with data from the newly identified RCTs when outcomes were reported in at least 3 trials and calculated relative and absolute measures of effect with corresponding 95% CIs. We used a fixed-effects model when outcomes were reported by fewer than 5 trials and a random-effects model (Hartung–Knapp–Sidik–Jonkman) when 5 or more trials reported on the outcome. Data were analyzed in R (R Foundation) (19). The magnitude of statistical heterogeneity was assessed with the I 2 statistic (I 2 > 75% may indicate substantial heterogeneity) (20).
We include updated meta-analyses, incorporating data from the newly published RCTs for the outcomes of mortality (all severity COVID-19), proportion recovered, proportion receiving mechanical ventilation at follow-up, serious adverse events, and any adverse event. We describe findings for SARS-CoV-2 clearance. Although this outcome was deemed an intermediate, nonclinical outcome, we include this information to address uncertainty about the effect of remdesivir on viral clearance and the potential implications on use of remdesivir on the basis of COVID-19 symptom duration.
Role of the Funding Source
This work is based on a living, rapid review done for the U.S. Department of Veterans Affairs (VA) Evidence Synthesis Program that concludes with this update (21). Funding for that review was provided by the Veterans Health Administration Office of Research and Development, Health Services Research and Development Service. The funding source assigned the topic but was not involved in data collection, analysis, manuscript preparation, or submission.
Results
The updated literature search identified 426 citations (Appendix Figure). We identified 2 new eligible publications: a subtrial by Ader and colleagues (DisCoVeRy) (15) and an RCT by Abd-Elsalam and colleagues (16). When added to the previous update that includes 6 RCTs and a subtrial, there are a total of 7 RCTs and 2 subtrials that assess effectiveness of remdesivir for COVID-19 (4–8, 12, 14–16).
Appendix Figure. Evidence search and selection.
RCT = randomized controlled trial.
Overview of All Randomized Trials (9 Trials)
Of the 7 RCTs and 2 subtrials evaluating remdesivir for COVID-19, the 2 new studies (1 RCT and 1 subtrial) add to the previous 5 studies (4 RCTs and 1 subtrial) comparing a 10-day course of remdesivir with control (placebo or standard care [SC]) (4, 5, 8, 14–16). Hence, our updated analyses focus on the 5 RCTs and 2 subtrials comparing a 10-day course of remdesivir with control (4, 5, 7, 8, 14–16). The remaining comparisons between 5-day course and either a 10-day course and/or SC (6, 7) did not have any new evidence. The previous summaries and conclusions from these are presented in summary tables. Details about study characteristics, outcomes, and harms are reported in Supplement Tables 3 to 8, and information on risk of bias is presented in Supplement Table 9.
New Findings From Ader and Colleagues (DisCoVeRy) and Abd-Elsalam and Colleagues
Ader and Colleagues (DisCoVeRy)
DisCoVeRy was a multicenter, open-label subtrial of Solidarity (15) done in Europe (Supplement Table 3). DisCoVeRy (n = 832) compared a 10-day course of remdesivir with SC for adults hospitalized with laboratory-confirmed COVID-19 with clinical hypoxia or need for oxygen supplementation (Supplement Table 10). Results from some DisCoVeRy participants (53%) had been included in the published Solidarity report (8). The primary outcome for the DisCoVeRy trial was clinical status at day 15 measured using the WHO 7-point ordinal scale, an outcome not reported in the Solidarity trial. Median symptom duration was 9 days. At baseline, nearly all patients were receiving at least supplemental oxygen, and 40% were receiving corticosteroids. Compared with SC, remdesivir did not result in a statistically significant improvement in clinical status on day 15 (odds ratio, 0.98 [95% CI, 0.77 to 1.25]). In addition, there was no statistically significant difference between remdesivir and SC in time to improvement, length of hospitalization, proportion needing ventilation on day 15, 28-day mortality, serious adverse events, or any adverse events. There was no effect of remdesivir on SARS-CoV-2 kinetics measured in the nasopharynx.
Abd-Elsalam and Colleagues
The study by Abd-Elsalam and colleagues was an open-label RCT done in Egypt (Supplement Table 3) (16). The study (n = 200) compared a 10-day course of remdesivir with SC for adults hospitalized with laboratory-confirmed COVID-19. The primary outcomes were length of hospital stay and mortality. The median symptom duration and patient stratification by baseline oxygen requirements were not reported. However, the mean baseline oxygen saturation, reported as 88.5%, was consistent with the National Institutes of Health and WHO definition of severe COVID-19 (Supplement Table 10). Remdesivir, compared with SC, resulted in a statistically significant reduction in median duration of hospitalization (10 vs. 16 days; P < 0.001) but did not reduce mortality (9% vs. 7%; P = 0.602). Remdesivir did not affect new need for ventilation. No serious adverse events were noted in either group.
Summary Findings
For summary findings, see Figures 1 and 2, the Table, the Appendix Table, and Supplement Tables 1 to 10.
Figure 1. Mortality for remdesivir 10-day course versus control (placebo or standard care).
ACTT-1 = Adaptive COVID-19 Treatment Trial; RR = risk ratio; SIMPLE-2 = Study to Evaluate the Safety and Antiviral Activity of Remdesivir [GS-5734] in Participants With Moderate Coronavirus Disease [COVID-19] Compared to Standard of Care Treatment.
Figure 2. Nonmortality outcomes for remdesivir 10-day course versus control (placebo or standard care).
ACTT-1 = Adaptive COVID-19 Treatment Trial; DisCoVeRy = Trial of Treatments for COVID-19 in Hospitalized Adults; ECMO = extracorporeal membrane oxygenation; RR = risk ratio; SIMPLE-2 = Study to Evaluate the Safety and Antiviral Activity of Remdesivir [GS-5734] in Participants With Moderate Coronavirus Disease [COVID-19] Compared to Standard of Care Treatment. Top. Proportion recovered. Middle. Need for invasive ventilation or ECMO. Bottom. Patients with ≥1 serious adverse events.
Remdesivir 10-Day Course Compared With Control (Placebo or SC) (7 Trials)
Of the 5 trials and 2 subtrials comparing a 10-day course of remdesivir with control, 2 used a placebo (4, 5) and 5 used SC as the control (7, 8, 14–16) (Supplement Table 3). Five RCTs included patients with severe and critical COVID-19 (4, 5, 8, 14, 15), 1 RCT included only patients with moderate disease (7), and 1 RCT included patients with unclear severity of disease (16). Six studies had a low risk of bias (4, 5, 7, 14–16), and 1 had a moderate risk of bias (8).
All-Cause Mortality
Our updated analyses, including new results from Abd-Elsalam and colleagues (16), confirm that remdesivir compared with control (placebo or SC) probably results in little to no difference in mortality (absolute risk difference [ARD], −0.7% [CI, −2.4% to 1.0%]) (moderate COE) (4, 5, 7, 8, 16) (Figure 1). A sensitivity analysis, with the addition of the results from the 392 patients from DisCoVeRy that were not previously included in the published Solidarity report, produced results similar to those of the primary analysis. Prior subgroup analyses for mortality by baseline oxygen support requirements remain unchanged (9) because the newly included RCT (16) did not stratify patients by baseline disease severity or oxygen needs.
Proportion of Patients Recovered
Updated analyses, including new results from DisCoVeRy (15), confirm that remdesivir, compared with control, probably results in a moderate increase in the percentage of patients who recovered by day 28 or 29 (ARD, 6.5% [CI, 3% to 10%]) (moderate COE) (4, 5, 7, 15) (Figure 2, A). Recovery was defined as not hospitalized (15), discharged from the hospital or hospitalization for infection control purposes only (4), or discharged from the hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care (5, 7).
Proportion with Clinical Improvement
Hospital Length of Stay
Percentage of Patients Hospitalized
Time to Recovery
Time to Clinical Improvement
Updated analyses, including new results from DisCoVeRy (15), confirm that remdesivir, compared with control, may result in a small reduction in median time to clinical improvement (clinical improvement was defined as days to improvement of 2 categories of the 7-point ordinal scale, ranging from 1 = not hospitalized and no limitations on activities to 7 = death) or hospital discharge up to day 29 (low COE) (5, 15).
Need for Ventilation or ECMO
Proportion Receiving Ventilation or ECMO at Follow-up
Our updated analyses, including new results from DisCoVeRy (15), show that remdesivir, compared with control, probably results in a small reduction in the proportion of patients receiving ventilation or ECMO at specific time points between days 11 and 15 (ARD, −4.5% [CI, −7.2% to −1.7%]) (moderate COE) (Figure 2, B) (4, 5, 7, 15).
New Need for Ventilation or ECMO
The inclusion of results from Abd-Elsalam and colleagues' study (16) with Solidarity confirms our prior conclusion that remdesivir, compared with control, probably results in little to no difference in new need for ventilation or ECMO within 28 days or 6 months (range of ARDs, 0.4% to 3.0%; 2 RCTs) (moderate COE) (Figure 2, B) (8, 16). On the basis of a sensitivity analysis, which included information from DisCoVeRy patients not previously included in the published Solidarity report, we concluded (due to inconsistency between RCT results) that remdesivir, compared with control, may result in little to no difference in new need for ventilation between 28 days to 6 months (3 RCTs) (8, 15, 16).
Adverse Events
Updated meta-analyses, including results from additional RCTs (14–16), show that remdesivir, compared with control, may lead to a small reduction in serious adverse events (ARD, −2.1% [CI, −6.5% to 2.2%]) (low COE) (Figure 2, C) (4, 5, 7, 14–16). Our last update found that remdesivir versus control probably results in a moderate reduction in serious adverse events (9). There was variation in how the trials reported serious adverse events, often including a combination of direct remdesivir toxicity and clinical findings consistent with COVID-19 progression (such as respiratory failure and need for endotracheal intubation). Updated meta-analyses, including results from 2 new RCTs (14, 15), show that remdesivir, compared with control, may result in a small increase in any adverse event (ARD, 4.9% [CI, −7.3% to 17.1%]; 5 RCTs) (low COE) (4, 5, 7, 14, 15).
Viral Clearance
Three RCTs assessed the effect of remdesivir on SARS-CoV-2 kinetics in the respiratory tract (5, 14, 15)—an intermediate outcome not assessed for COE (Supplement Table 6). All studies measured SARS-CoV-2 viral loads sequentially for 14 to 28 days after randomization using a quantitative, real-time, reverse transcriptase polymerase chain reaction test. All 3 RCTs showed that regardless of specimen site or collection methods (upper or lower airways; nasopharyngeal or oropharyngeal swabs or expectorated sputum), there was no statistically significant difference in the kinetics of SARS-CoV-2 load with remdesivir compared with control. All 3 RCTs also showed that the effect of remdesivir on SARS-CoV-2 clearance did not vary by symptom duration (stratified as ≤10 or >10 days [5]; <7 or ≥7 days [14]; or ≤7 days, −14 days, or >14 days [15]) or by baseline oxygen requirements (15).
Duration of Remdesivir Therapy: 5 Versus 10 Days (2 Trials)
No new RCTs compared a 5-day with a 10-day course of remdesivir. Hence, our prior conclusions, based on 2 RCTs (6, 7), remain unchanged (9) (Table and Appendix Table).
Discussion
This final update of our living review updates some findings comparing the effect of a 10-day course of remdesivir with control (placebo or SC) (4, 5, 7, 8, 14–16). The newly included RCTs strengthen previous findings on the benefit of remdesivir on the proportion of patients receiving ventilation or ECMO at follow-up but decreases the strength of previous findings on the reduction of serious adverse events with remdesivir. Another major change for this update was the low certainty of an increase in any adverse event with remdesivir (compared with a previous finding of little or no change in any adverse event). Other findings of the effect of a 10-day course of remdesivir (intervention) compared with either placebo or SC (control) are confirmed or unchanged.
Despite the reported strong antiviral effect of remdesivir against SARS-CoV-2 in preclinical models (22), 3 RCTs consistently show that remdesivir does not accelerate viral clearance in upper or lower airways compared with control, regardless of symptom duration. Another study published after our search date reported similar findings among outpatients with COVID-19 with symptoms for 7 days or less (23). These results suggest that remdesivir's effectiveness is not related to viral load clearance and that using SARS-CoV-2 clearance in upper and lower airways is not a valid surrogate for clinical outcomes (24).
Cost-effectiveness models assume that remdesivir shortens duration of hospitalization for patients with COVID-19 (25). Contrary to this assumption, 1 large propensity-matched retrospective cohort study among veterans hospitalized at VA medical centers (n = 2344) found that remdesivir treatment was associated with prolonged hospitalization without improved survival (26). The clustering of discharges suggested that patients ready for medical discharge were hospitalized solely to complete the prescribed course of remdesivir—a practice inconsistent with RCT protocols and treatment guidelines (4, 27, 28).
Given that this is our last living review update, we note ongoing trials of remdesivir for COVID-19 evaluating formulations and populations not previously studied, which may alter practice and policy. These include inhaled and oral formulations of remdesivir and studies including previously excluded populations (pregnant women, children, and patients with renal dysfunction) (29). In addition, 1 placebo-controlled RCT was published after our last search date, which is the only study done among outpatient adults and assessing the effect on hospitalizations. The study evaluated remdesivir given intravenously daily for 3 days to high-risk, unvaccinated outpatients with COVID-19 with 7 days or less of symptoms (23). Compared with placebo, remdesivir reduced COVID-19–related hospitalization at day 28 (0.7% [2 of 279] vs. 5.3% [15 of 283]; P = 0.008). There were no deaths in either group. The study enrolled patients before the emergence of the Delta or Omicron variants of SARS-CoV-2 as the dominant strain and was terminated early due to “the changing epidemiology and adoption of additional treatment options at the time” (23, 30).
In conclusion, in hospitalized adults with COVID-19, remdesivir probably results in little to no difference in mortality. However, remdesivir probably increases the proportion of patients recovered and may reduce time to clinical improvement and length of hospitalization. Remdesivir may lead to a small reduction in serious adverse events but may lead to a small increase in any adverse event. Compared with a 5-day course of remdesivir, a 10-day course may have little to no benefit and has higher drug cost among patients not requiring mechanical ventilation or ECMO.
Supplemental Material
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Published In
Annals of Internal Medicine
Volume 175 • Number 5 • May 2022
Pages: 701 - 709
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Published online: 1 March 2022
Published in issue: May 2022
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Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points. Ann Intern Med.2022;175:701-709. [Epub 1 March 2022]. doi:10.7326/M21-4784
Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points. Ann Intern Med.2022;175:701-709. [Epub 1 March 2022]. doi:10.7326/M21-4784
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Before assessing effectiveness and safety profile of remdesivir consider its drug-drug interactions and side effects
We read with interest the update of a living review article by Kaka et al. about remdesivir as a treatment of coronavirus disease-19 (COVID-19) in hospitalised adults.[1] Evaluated were five randomised control trials (RCTs) and two subtrials.[1] It was concluded that remdesivir “probably results in little to no difference in mortality and increases the proportion of patients recovered”, that remdesivir “may reduce time to clinical improvement, and “may lead to small reductions in serious adverse events but may result in a small increase in any adverse event”.[1] The study is appealing but raises concerns.
We do not agree that the only limitation of the study is the difference in definitions of COVID-19 severity and outcomes between the included RCTs.[1] A limitation not considered is the interaction between remdesivir and the other drugs given to COVID-19 patients and the drugs patients were regularly taking prior to admission. Hospitalised COVID-19 patients frequently receive a polypharmacy not only for COVID-19 but also because they are frequently polymorbid. Effectiveness and side effect profile may strongly depend on interactions with other drugs, particularly those which are eliminated via the same pathway in the liver and those which exert their effects by the same mechanisms as remdesivir.
Another limitation not considered in the calculations and considerations are the side effects of remdesivir itself. Recent studies in three patients have shown that remdesivir can be associated with bradycardia and QTc prolongation.[2] Bradycardia in these three patients did not respond to atropine.[2] Hearth rate returned to normal with discontinuation of remdesivir.[2] Several studies have shown that remdesivir can be hepatotoxic and can elevate liver enzymes,[3] as with other nucleoside analogues. Remdesivir can cause cellular stress responses and injuries in hepatocytes through drug-drug or alcohol-drug interactions. In a study of 2922 reports with remdesivir registered in FAERS, 493 with renal/urinary adverse effects were reported.[4] Use of remdesivir was associated with and increased chance of reporting renal/urinary disorders regardless of gender and age (2.53; 95%CI 2.10-306).[4] By obtaining data from individual safety reports (ICSRs) of the WHO database (VigiBase) about remdesivir, a total of 2107 cases of neuropsychological adverse reactions (ADRs) such as anxiety, seizures, lethargy, agitation, ischemic stroke, hemiparesis, were reported.[5]
Overall, the interesting study has limitations which challenge the results and their interpretation. Real world data about the efficacy and side effects of drugs need to be included before assessing effectiveness and safety profile of a drug.
References
1. Kaka AS, MacDonald R, Linskens EJ, Langsetmo L, Vela K, Duan-Porter W, Wilt TJ. Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points. Ann Intern Med. 2022 Mar 1. doi: 10.7326/M21-4784.
2. Shirvani M, Sayad B, Shojaei L, Amini A, Shahbazi F. Remdesivir-Associated Significant Bradycardia: A Report of Three Cases. J Tehran Heart Cent. 2021 Apr;16(2):79-83. doi: 10.18502/jthc.v16i2.7390.
3. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Wang Y, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B, Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. doi: 10.1016/S0140-6736(20)31022-9.
4. Silva NAO, Zara ALSA, Figueras A, Melo DO. Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database. Cad Saude Publica. 2021 Nov 12;37(10):e00077721. doi: 10.1590/0102-311X00077721.
5. Lee S, Yang JW, Jung SY, Kim MS, Yon DK, Lee SW, Kang HC, Dragioti E, Tizaoui K, Jacob L, Koyanagi A, Salem JE, Kostev K, Lascu A, Shin JI, Kim JH, Smith L. Neuropsychological adverse drug reactions of Remdesivir: analysis using VigiBase, the WHO global database of individual case safety reports. Eur Rev Med Pharmacol Sci. 2021 Dec;25(23):7390-7397. doi: 10.26355/eurrev_202112_27435.
Disclosures:
none
Author Response to Dr. Finsterer
Response to Dr. Finsterer:
We thank Dr. Finsterer for his comments. While helpful, our conclusions do not change.
Dr. Finsterer states that hospitalized COVID-19 patients frequently receive polypharmacy for COVID-19. Additionally, he notes they frequently have multiple comorbidities and that remdesivir’s effectiveness and side effect profile may strongly depend on interactions with other drugs, particularly those eliminated via the same pathway in the liver and those which exert their effects by the same mechanisms. Thus, he questions our reported conclusions about benefits and harms.
We agree that hospitalized COVID-19 patients frequently have comorbidities and receive other medications for COVID-19. However, included studies were conducted prior to currently available effective agents. Additionally, remdesivir has few known drug-drug interactions, and randomized controlled trials (RCTs) (and our report) described inclusion and exclusion criteria regarding patient characteristics and use of concomitant medications (1). Furthermore, in RCTs the distribution of comorbidities and concomitant medications, as well as other potentially confounding variables, should be similar between intervention and control groups. Lastly, in our original report, we described, in detail, FDA guidance for patients in whom remdesivir should be used with caution or is contraindicated and medications contraindicated with remdesivir (2).
Dr. Finsterer also comments that another limitation not considered in the calculations and considerations are the side effects of remdesivir itself. We reported serious adverse effects and all adverse effects in both remdesivir and control groups (as provided by RCTs) (3). We also described FDA guidance on adverse effects including hepatotoxicity warranting cessation of remdesivir (2). We agree that post marketing surveillance and “real world data” is critical to characterize rarer side-effects of new drugs not detected in RCTs, such as bradycardia with remdesivir and to assess effectiveness in vaccinated patients and those receiving known effective agents. This knowledge can be used to update FDA information and clinical practice (1).
References:
Should Remdesivir Be Used for the Treatment of Patients with COVID-19? Rapid, Living Practice Points From the American College of Physicians (Version 2, Update Alert 3)
This is an update of the American College of Physicians’ living, rapid practice points on the use of remdesivir for treatment of coronavirus disease 2019 (COVID-19) (1-3). This update is based on an updated living, rapid systematic review that included studies published through 19 October 2021 (4) and identified 2 new studies meeting inclusion criteria. One was a primary randomized controlled trial (RCT) (5). The second was a sub-study (6) of a primary RCT (7) that was already included in version 2 of the practice points and systematic review (1-3, 8-10) but assesses new data on outcomes of interest not evaluated by the primary study (7). Both new studies evaluated a 10-day course of remdesivir versus standard care. In addition, this update includes data for serious adverse events and any adverse events from 1 sub-study (11) not reported in the previous evidence review (10). No new evidence has been identified assessing a 5-day course of remdesivir compared with placebo/standard care or compared with a 10-day course. The Supplement (available at Annals.org) summarizes the key questions and practice points development process, as well as provides an updated evidence overview and summary of findings, clinical considerations, and evidence gaps.
Practice Points
The following practice points are based on current best available evidence about the effectiveness and harms of remdesivir and its variability by symptom duration, disease severity, and treatment duration in patients with COVID-19. The target patient population includes all hospitalized, nonpregnant, adult patients with COVID-19. Although an important area of research, these practice points do not address treatment with remdesivir in outpatient settings.
Practice Point 1: Consider remdesivir for 5 days to treat hospitalized patients with COVID-19 who do not require invasive ventilation or ECMO.
Updated Rationale
The evidence update did not result in any changes to our previous overall assessment as there continues to be an overall net benefit of remdesivir with both a 5-day (1, 2, 8, 9) and a 10-day course (1, 3, 4, 8, 10), as well as evidence to suggest that 5 days of treatment may be as effective as 10 days (1, 8).
None of the new studies evaluated a 5-day course of remdesivir. Assessing the updated evidence evaluating a 10-day course of remdesivir compared to placebo or standard care (4-6, 11), we still judged there to be an overall net benefit (low- to moderate-certainty evidence) for a 10-day course across all outcomes: recovery (modest increase), hospital length of stay (modest reduction), clinical improvement (modest increase), time to recovery (large reduction), time to clinical improvement (slight reduction), need for invasive ventilation/ECMO at follow-up (slight reduction), and fewer serious adverse events (slight reduction; previously a modest reduction), with no differences in mortality or the new need for mechanical ventilation/ECMO and a slight increase in any adverse events (previously little to no difference).
The new studies did not evaluate a 5-day course compared to a 10-day course. Thus, our previous conclusion that a 5-day course compared with a 10-day course (1, 8) may reduce mortality (slightly), time to recovery (slightly), and need for invasive ventilation/ECMO at follow-up (slightly), as well as increase recovery (modestly) and clinical improvement (modestly), with fewer serious adverse events and any adverse events (both modestly), remains unchanged. In addition, previously reported patient compliance data from 1 study further supports clinical advice for considering the use of a 5-day course; of patients allocated to a receive a 10-day course versus placebo, less than half (41.2%) received all 10 doses with an even lower percentage of patients (38.1%) receiving all 10 doses because they recovered and were discharged from the hospital (12, 13).
Previous evidence comparing a 10-day course of remdesivir with placebo or standard care showed a modest reduction in mortality among patients requiring supplemental oxygen (but not invasive ventilation) and little to no difference in mortality in patients not requiring supplemental oxygen at the time a 10-day course was initiated (1, 8) Considering the expectation that most patients with a diagnosis of COVID-19 are admitted with respiratory signs and symptoms, we determined that the evidence insufficient to advise against considering the use of remdesivir in patients who do not require supplemental oxygen at the time of drug initiation.
Practice Point 2: Consider extending the use of remdesivir to 10 days to treat hospitalized patients with COVID-19 who develop the need for invasive ventilation or ECMO within a 5-day course
Updated Rationale
Our previous conclusion remains unchanged: evidence suggests that there is an overall net benefit for a 10-day course of remdesivir (1, 3, 4, 8, 10) and there is a reduction in mortality with extension of remdesivir treatment to 10-days in hospitalized patients with COVID-19 who progress to requiring ventilation or ECMO by day 5 of remdesivir that outweighs potential harms (8, 14).
The updated findings (4-6, 11) show an overall net benefit (low- to moderate-certainty evidence) for a 10-day course across all outcomes: recovery (modest increase), hospital length of stay (modest reduction), clinical improvement (modest increase), time to recovery (large reduction), time to clinical improvement (slight reduction), need for invasive ventilation/ECMO at follow-up (slight reduction), and fewer serious adverse events (slight reduction), with no differences in mortality or the new need for invasive ventilation/ECMO and a slight increase any adverse events. In addition, a previously reported post-hoc analysis assessing variation in disease severity (respiratory support requirements) between a 5-day and 10-day course of remdesivir suggested that continued treatment through 10 days resulted in lower mortality among patients who progressed to requiring invasive ventilation or ECMO at day 5. However, no improvement was observed in mortality among patients who were receiving non-invasive positive-pressure ventilation or high- or low-flow oxygen or who were breathing ambient air (8, 14).
Practice Point 3: Avoid initiating remdesivir to treat hospitalized patients with COVID-19 who are already on invasive ventilation or ECMO.
Reaffirmed Rationale
The update did not identify any relevant studies for practice point 3; thus, our previous conclusion remains unchanged. Previous evidence from a pooled subgroup analysis in the systematic review found that patients receiving invasive ventilation or ECMO at the time of drug initiation may experience a modest increase in mortality (8) and a post-hoc finding in one study demonstrated no improvement in time to recovery among patients receiving invasive ventilation or ECMO at baseline (12, 13) with a 10-day course versus placebo or standard care. These findings are consistent with our current understanding of COVID-19 progression that patients who are admitted on invasive ventilation or ECMO have likely progressed beyond the viral stage of the illness to the inflammatory stage and are less likely to improve from antivirals; hence, it is important to avoid any additional toxicity from remdesivir, in the absence of demonstrated benefit and possible harm.
Retirement from the Living Status
The SMPC has decided to retire this topic from living status in order to balance current priorities with existing resources (15), considering that surveillance was originally planned through December 2021 and that the last 3 updates did not result in important changes to conclusions.
References
Disclosures:
Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-4810. All financial and intellectual disclosures of interest were declared, and potential conflicts were discussed and managed. Dr. Obley participated in discussion of the practice points but was recused from authorship and voting due to a moderate-level conflict of interest (author of supporting systematic review). Drs. Dunn, Kansagara, and Marcucci participated in discussion but were recused from authorship and voting due to moderate-level conflicts of interest (authors of recent relevant systematic reviews). A record of disclosures of interest and management of conflicts is kept for each Scientific Medical Policy Committee meeting and conference call and can be viewed at www.acponline.org/about-acp/who-we-are/leadership/boards-committees-councils/scientific-medical-policy-committee/disclosure-of-interests-and-conflict-of-interest-management-summary-for-scientific-medical-policy.
The development of living systematic review may require more rigorous thinking and assessment
We read with interest Kaka and his colleagues’ remarkable and well-organized series of living systematic reviews, (1) to which they have devoted a great deal of effort. The series was updated several times and found that in hospitalized adults with COVID-19, remdesivir made little difference in mortality and increased the proportion of patients who recovered. Remdesivir may shorten the time to clinical improvement and may lead to small decreases in serious adverse events but may contribute to a slight increase in any adverse events. However, the conduct of this living systematic review series provoked us to reflect.
Although both rapid reviews and traditional systematic reviews can become living reviews, there is still a difference in the methodological development of the two, as well as in their transformation into living reviews. (2) The authors’ series of studies were planned to be conducted in the form of living systematic reviews, and the specification followed the production of systematic reviews. However, several statements in the text refer to it as a “living rapid review”, which may be inappropriate.
Second, a series of studies for living reviews often require planning and scheduling. (3) The authors planned in their initial report (4) that the living process needed to be achieved by bimonthly searches. However, the subsequent studies did not follow this guideline very well. We strongly acknowledge that the authors assessed the value of the evidence and the feasibility of inclusion in each update of the retrieved evidence. Although there was no prior published study protocol, Kaka stated in the fifth update that this was the last update as planned and that the follow-up would be conducted using cumulative Meta-analysis when feasible. (1) Has the study series achieved the desired goals of the living program? What results are expected may not yet be known to the reader. We are not yet sure if this is appropriate and why the endpoint of the series was not determined with a benefit boundary but with a time or number of updates limit. (5)
In conclusion, we still appreciate the tremendous efforts of the authors for this project. However, the actual process of living systematic review may require more rigorous consideration and assessment. We expect this method to gain more significant standardization and progress in practical exploration.
References
Author Response to Zheng et al.
We thank Zheng et al. for their comments on the quality of the living review and efforts involved.
The authors question whether our series of systematic reviews are appropriately called “rapid living” reviews (1, 2). Experts propose defining a rapid living systematic review as “a dynamic method of knowledge synthesis that allows for the constant updating of new emerging evidence and refinement of its methodological quality” (3). We believe our series of reviews meet that definition given the rapidly evolving evidence, informational needs and publication practicalities related to COVID-19. Our goal was to rapidly synthesize new evidence on the effectiveness and harms of remdesivir for adults with COVID-19, in order to inform the Department of Veterans Affairs (VA) as well as the American College of Physicians-Scientific Medical Policy Committee (ACP-SMPC) practice points (4).
The authors inquire about the scheduling of searches and updates, the choice of a time endpoint for the living review, and whether the series of reviews achieved the desired goals. Our initial protocol planned to update our literature search bimonthly to include publications from January 2020 through December 2021. We subsequently shortened this interval to search weekly to rapidly identify any new information that might require updates. Our actual update interval ranged from 2 to 3 months and was based in part on adaptation in living review methodology, as well as feasibility in coordinating our systematic review updates with peer reviews through the VA-Evidence Synthesis Program (ESP), the ACP-SMPC and their corresponding practice points, and Annals. The decision to retire the living review was discussed with the VA-ESP, ACP-SMPC, and Annals prior to our last update. Given the extensive included evidence and limited ongoing trials there was concurrence that the goals of the living review were met. New research was unlikely to change evidence certainty or policy/clinical decisions. Thus, both our living review and the ACP-SMPC practice points were retired.
We agree with Zheng et al. that developing frameworks for living systematic reviews and corresponding policy statements will gain more standardization with time. However, our experience in this process highlights that “one size does not fit all”. A value in living reviews is their ability to rapidly, yet rigorously and transparently, adapt to evolving information and informational needs rather than to rigidly adhere to a previously determined prescriptive formula. Such a process optimizes review and policy resources as well as clinical and research priorities.
REFERENCES
1. Wilt TJ, Kaka AS, MacDonald R, Greer N, Obley A, Duan-Porter W. Remdesivir for Adults With COVID-19 : A Living Systematic Review for American College of Physicians Practice Points. Ann Intern Med. 2021;174(2):209-20.
2. Kaka AS, MacDonald R, Linskens EJ, Langsetmo L, Vela K, Duan-Porter W, et al. Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points. Ann Intern Med. 2022;175(5):701-9.
3. Negrini S, Ceravolo MG, Cote P, Arienti C. A systematic review that is ``rapid'' and ``living'': A specific answer to the COVID-19 pandemic. J Clin Epidemiol. 2021;138:194-8.