Jose Chacko, Gagan Brar
Meta-analysis of randomized controlled trials on tocilizumab in COVID-19
Snow TAC, et al. Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials. Intensive Care Med. 2021 Jun;47(6):641-652. doi: 10.1007/s00134-021-06416-z.
Interleukin-6 antagonism has been one of the therapeutic approaches that have evinced interest in COVID-19 treatment. The REMAP-CAP1 and RECOVERY2 trials had revealed favorable clinical outcomes, including improved survival with tocilizumab, an interleukin-6 inhibitor. However, considering the relatively lower levels of interleukin-6 in COVID-19 compared to bacterial sepsis, questions remain regarding the efficacy of interleukin-6 antagonists.
Snow et al. performed a meta-analysis of randomized controlled trials (RCT) that evaluated the use of tocilizumab in COVID-19.3 Trials were included if tocilizumab was compared with placebo or with standard care as the control arm. The authors identified 10 RCTs that investigated the efficacy of tocilizumab in COVID-19.
Among the included trials, non-invasive ventilation (NIV) was used in seven, high-flow nasal cannula in five, and supplemental oxygen alone in two trials. Nine trials used tocilizumab, one used sarilumab; either drug was used in another trial. The dose of tocilizumab administered was 8 mg/kg in eight trials; in seven trials, a repeat dose was administered if no response was observed. A dose of 6 mg/kg was used in one of the included trials. Four trials used placebo control while tocilizumab was compared to standard care in others. Corticosteroids were used in 72% of patients.
The primary outcome was mortality at 28–30 days. Mortality was 24.4% in the tocilizumab arm compared with 29% in the control arm (OR: 0.87; CI: 0.74–1.1, P = 0.007; I2 = 10%).
Among the secondary outcomes, progression to mechanical ventilation was significantly lower with tocilizumab compared to the control group [8.7 vs. 10.5%; 0.7 (CI: 0.54–0.89), P = 0.04]. Progression to the requirement for intensive care was not different between groups.
The composite outcome of the requirement for intensive care or progression to mechanical ventilation was significantly lower with tocilizumab compared to controls [28.9 vs. 36.6%; OR: 0.7 (0.59–0.89), P = 0.002]. Meta-regression revealed a weak relation between tocilizumab treatment and the risk of mortality. A sensitivity analysis including trials with a low risk of bias did not reveal a significant difference in mortality between groups.
- The RECOVERY and REMAP-CAP trials contributed to a 77.3% of the weight of the meta-analysis
- Some studies allowed a second dose, but outcomes were not analyzed based on the dose administered
- The use of corticosteroids varied between trials. The RECOVERY trial suggested that the combination of corticosteroids and tocilizumab was effective, while tocilizumab alone may be ineffective
- Adverse events may have been underreported; hence, possible harm from tocilizumab remains unclear
- Most trials were open-label, which may have contributed to bias
- It is important to evaluate longer-term outcomes – perhaps at 6 months, particularly considering the possibility of infective complications related to immunosuppression which may cause long-term morbidity and mortality
Remdesivir in COVID-19: mountain out of a molehill?
Ohl ME, et al. Association of Remdesivir Treatment With Survival and Length of Hospital Stay Among US Veterans Hospitalized With COVID-19. JAMA Netw Open. 2021 Jul 1;4(7):e2114741. doi: 10.1001/jamanetworkopen.2021.14741
Following the ACTT-1 trial that showed a reduced duration of hospitalization,4 remdesivir has been extensively used in hospitalized patients with COVID-19. However, the results from controlled studies have been conflicting and the living guidelines of the World Health Organization (WHO) does not currently recommend remdesivir treatment in hospitalized patients with COVID-19.5
Against this background, Ohl et al. conducted a retrospective cohort study of patients who tested positive for COVID-19 by RT-PCR from the Veterans Health Administration hospitals in the US between May 1 and Oct 8, 2020.6 The authors identified 7388 patients with first hospitalization for COVID-19 during this period. Patients who tested positive by RT-PCR within 14 days prior to and within 5 days of admission were included. After the exclusion of 1490 patients for various reasons, 5898 patients were included in the initial analysis. Exposure to remdesivir was studied as a time-dependent variable. The outcomes studied were all-cause mortality within 30 days of initiation of remdesivir treatment and the time to hospital discharge.
Patients who received remdesivir and those who did not were compared by propensity score matching. Each patient who received remdesivir treatment on a given hospital day was matched to a similar patient who did not receive remdesivir. The Cox proportional hazards regression model was used to estimate differences in outcomes in the matched cohort. To ensure consistency of results, the authors used an alternate approach using a marginal structural model with inverse probability of treatment rates by hospital day.
In the initial cohort of 5898 patients, 2374 (40.3%) received remdesivir. Patients who received remdesivir were older, more likely to be white, more likely to have COPD, and were more severely ill at admission. Propensity matching was performed on 1172 patients who received remdesivir and an equal number of patients who did not. Patients in the matched groups were similar in race, ethnicity, comorbidities, the month of admission, the severity of illness on the hospital day of matching, and laboratory values.
Overall, 267 (11.4%) patients died within 30 days of admission. In the remdesivir group, 143 (12.2%) patients died compared to 124 (10.6%) in the matched cohort (log rank for p=0.26, not significant). The hazard ratio for mortality within 30 days was similar in a Cox proportional hazards model. The 30-day mortality was also similar in subgroups of patients who received dexamethasone compared to those who did not. Sensitivity analysis of patients who were administered remdesivir within 48 h of admission compared to those who received it later revealed no difference in mortality.
The median time to hospital discharge in remdesivir-treated patients was longer in the propensity-matched cohort [6 (4-12) vs. 3 (1-7) days; (P = 0.001)]. This finding suggested that treatment with remdesivir resulted in a delay in hospital discharge. The results were similar using the alternate, marginal structural model.
This observational cohort study with propensity matching revealed no difference in 30-d survival, while the time to hospital discharge was longer in patients who received remdesivir compared to a propensity-matched control group. These findings contrast with the ACTT-1 trial, which showed a significant reduction in the duration of hospitalization with remdesivir. The findings of this study concur with previous studies that did not reveal improved survival with the use of remdesivir. Besides, the WHO-sponsored SOLIDARITY trial had revealed no difference in hospital mortality nor the duration of hospitalization with the use of remdesivir. The present study, although observational in nature, casts doubts on the efficacy of remdesivir in improving clinical outcomes.
- Possibility of bias from unidentified confounders, as in any observational cohort study, although propensity matching was carried out
- Among the large cohort, propensity matching was possible only in 1172 patients in each group (49.5% of the entire cohort)
- Propensity-matched patients were less severely ill compared to the unmatched cohort of patients. Most of the severely ill patients may have received remdesivir anyway, and were not included in the propensity-matched cohort
- No data were available on the duration of oxygen therapy prior to remdesivir administration. This is important because remdesivir administration during the early stage of viral replication is more likely to be beneficial
- Importantly, the study may simply reflect the fact that hospitalization in remdesivir-treated patients may have been continued solely to complete the treatment course (although they may have been well enough to be discharged)
Ivermectin in COVID-19: yet another addition to the (growing) list of ineffective therapies?
López-Medina E, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 2021 Apr 13;325(14):1426-1435. doi: 10.1001/jama.2021.3071
Based on its antiviral effect against SARS-CoV-2 in animal studies and in vitro, ivermectin is widely prescribed in mild COVID-19 infection. López-Medina et al. conducted this RCT to evaluate whether ivermectin would hasten recovery if administered early in patients with mild COVID-19 infection.
Patients were identified by random sampling from a database, including patients who tested positive for COVID-19 by RT-PCR or rapid antigen testing. Patients were within 7 days of symptom onset and had mild disease, defined as being on home treatment or hospitalized, but not requiring high-flow nasal oxygen or mechanical ventilation. In the intervention group, ivermectin, 300 μg/kg of body weight per day, was administered orally for a period of 5 days. The control group received placebo. A total of the 476 patients underwent randomization, with 238 assigned to each group. Baseline characteristics were similar between groups, and most patients (58.3%) underwent home treatment.
The primary outcome was the time taken from randomization to complete resolution of symptoms evaluated during a 21-day period of follow-up. Symptoms were assessed using the 8-category ordinal scale proposed by the WHO. The time to symptom resolution was not significantly different between ivermectin-treated and placebo groups median [10 vs. 12 days; difference, −2 days (IQR, −4 to 2)]. Among the secondary outcomes, deterioration by 2 or more points on the ordinal scale was not significantly different between groups [odds ratio for deterioration, 0.56 (95% CI, 0.16 to 1.93)]. No significant difference was observed in the number of patients who required escalation of treatment (ivermectin vs. placebo: 2% vs. 5%). The incidence and the duration of fever were also similar between groups. One patient, who received placebo, died during the period of follow-up. Adverse events were few and similar between groups; none were deemed to be related to the study drug.
- The primary outcome was changed from the efficacy of ivermectin in preventing clinical deterioration to the time taken for complete resolution of symptoms, considering the low incidence of clinical deterioration
- The trial may have been underpowered to detect a lower, but clinically important reduction in the time to symptom resolution with ivermectin
- Time to viral clearance was not evaluated
- Self-reporting of symptoms may have been cofounded by subjectivity bias
- The median age of study participants was 37 years; the likely effect of ivermectin in an older subgroup of patients remains unexplored
The continued infatuation with cytokine removal in critically ill patients…
Scharf C, et al. Can the cytokine adsorber CytoSorb® help to mitigate cytokine storm and reduce mortality in critically ill patients? A propensity score matching analysis. Ann Intensive Care. 2021 Jul 22;11(1):115. doi: 10.1186/s13613-021-00905-6.
Historically, there has been continued enthusiasm with cytokine removal, particularly in septic patients with multiorgan failure. Besides source control, antibiotic therapy, and supportive care, inhibition of the “cytokine storm” has been postulated to ameliorate organ dysfunction and improve clinical outcomes. The cytokine adsorber, Cytosorb® (CS) has been one of the modalities of cytokine removal currently in widespread use, albeit without firm evidence.
Scharf et al. conducted a single center, retrospective observational, propensity-matched study to evaluate the efficacy of Cytosorb®. Patients with interleukin-6 (IL-6) levels of more than 10,000 pg/ml were screened. A total of 143 patients with IL-6 levels of more than 10,000 pg/ml were identified; 38 patients received Cytosorb® therapy while 105 did not. The Cytosorb® therapy was continued for a minimum duration of 90 minutes. In the entire cohort, the underlying etiology included septic shock (47.4%), acute respiratory distress syndrome (36.8%), and polytrauma (7.9%).7
The IL-6 levels decreased significantly by 79.1% during Cytosorb® therapy. Furthermore, the norepinephrine dose also reduced significantly by 27.7%. No change was observed in the CRP or the lactate levels.
Propensity matching was performed with the requirement for ECMO therapy, renal replacement therapy and the day 0 SAPS II score, IL-6 and lactate levels, and the dose of norepinephrine. Nineteen propensity-matched patients who received Cytosorb® therapy were compared with an equal number of patients who did not. The interleukin-6 levels reduced significantly in both groups of patients. However, there was no difference in the relative reduction of IL-6 levels between the two groups. There was no significant difference in the requirement for norepinephrine between groups. The 48-h and in-hospital mortality were also similar. The authors concluded that Cytosorb® therapy had no impact on IL-6 levels, hemodynamic stability, or mortality in this retrospective cohort study.
The study carries with it all the limitations of a retrospective observational study. Although the authors performed propensity matching, the resulting sample size was too small (19 matched pairs) to arrive at firm conclusions. The increase in IL-6 levels was due to varying etiology; no disease-specific conclusions can be drawn.
1. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021;384(16):1491-1502. doi:10.1056/NEJMoa2100433
2. Abani O, Abbas A, Abbas F, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 2021;397(10285):1637-1645. doi:10.1016/S0140-6736(21)00676-0
3. Snow TAC, Saleem N, Ambler G, Nastouli E, Singer M, Arulkumaran N. Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials. Intensive Care Med. 2021;47(6):641-652. doi:10.1007/s00134-021-06416-z
4. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 – Preliminary Report. N Engl J Med. Published online May 22, 2020. doi:10.1056/NEJMoa2007764
5. Therapeutics and COVID-19: living guideline. Accessed August 1, 2021. https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-therapeutics-2021.2
6. 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
7. Scharf C, Schroeder I, Paal M, et al. Can the cytokine adsorber CytoSorb® help to mitigate cytokine storm and reduce mortality in critically ill patients? A propensity score matching analysis. Ann Intensive Care. 2021;11(1):115. doi:10.1186/s13613-021-00905-6