Remdesivir & Tocilizumab in COVID-19 – Have we gone too far?

Consider using remdesivir for adults hospitalised with moderate to severe COVID-19 who do not require ventilation.

Do not start remdesivir in adults hospitalised with COVID-19 who require ventilation.

WHO determined that there was a lack of evidence demonstrating an improvement in patient-relevant outcomes when using remdesivir, such as mortality, need for mechanical ventilation, and time to clinical improvement.

Remdesivir is not recommended in adult patients diagnosed with COVID-19.

A recently published retrospective study in JAMA –

Association of Remdesivir Treatment With Survival and Length of Hospital Stay Among US Veterans Hospitalized With COVID-19

Methods

A retrospective cohort study of patients who tested positive for COVID-19 from the VHA hospitals in the US between May 1 and Oct 8, 2020. The authors identified 7388 patients with the first hospitalization for COVID-19 during this period. Patients were RT-PCR within 14 days prior to admission or tested positive during the admission. Out of this, 1490 were excluded for various reasons: first RT-PCR positive test was after 5 days of admission, no primary care visits to the VHA for 2 years, admitted to hospice, missing values for liver and renal function tests. Thus, 5898 patients were included in the initial analysis. Exposure to remdesivir was studied as a time-dependent variable. Outcomes studied were all-cause mortality within 30 days of initiation of remdesivir treatment and the time to hospital discharge.

Variables considered for risk adjustment were age, gender, race, ethnicity, co-morbidities, time of RT-PCR testing, the use of mechanical ventilation, requirement for ICU admission, lab values including liver and renal function tests, WCC; vital signs including temperature, blood pressure, respiratory rate, and oxygen saturation, outpatient medications prior to admission, concurrent medications used during hospital admission, and the month of admission. To compare patients who received remdesivir to those who did not, propensity score matching was employed. 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. Patients who were initiated on remdesivir treatment later were censored. To ensure consistency of results, they used an alternate approach using a marginal structural model with inverse probability of treatment rates by hospital day.

Results

The initial cohort of 5898, 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. 1172 patients who received remdesivir were matched by propensity matching to an equal number of patients who did not receive remdesivir. 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 the lab values.

ICU admission, requirement for mechanical ventilation were similar between the matched groups. Patients with an oxygen saturation of less than 94% were also similar between groups. The use of dexamethasone as concurrent treatment was also similar between groups.

Outcomes

A total of 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). Similar hazard ratios for mortality within 30 days 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.

Remdesivir-treated patients had a longer median time to hospital discharge after matching:  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. Hazard ratio for death within 30 days: 0.98 (0.71–1.35); hospital discharge: 0.72 (0.53–0.97).

Remdesivir treatment in COVID-19 patients resulted in a longer duration of hospitalization and did not lead to improved survival.

These findings are in contrast to the ACTT-1 trial, which showed a significant reduction in the duration of hospitalization with remdesivir. The findings of this study concurred with previous studies that did not reveal improved survival with the use of remdesivir. Besides, the SOLIDARITY trial showed no difference in hospital mortality nor in the duration of hospitalization. A couple of RCTs published later on, have also been equivocal regarding the efficacy of remdesivir. This study casts doubts on the efficacy of remdesivir in improving clinical outcomes.

Limitations

• Possibility of bias from unidentified confounders, as in any observational cohort study, although propensity matching was carried out.
• Out of 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 on the duration of oxygen therapy prior to remdesivir administration. This is important because 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 only to complete the treatment course (although they may have been well enough to be discharged).

Our summary – 

There is no enough evidence to recommend the routine use of remdesivir in patients admitted with COVID-19 and requiring oxygen therapy.

Tocilizumab in COVID-19

All guidelines recommend using tocilizumab along with steroids in severely ill patients with covid-19.

However, there is no data on long term outcomes in patients who received Tocilizumab during COVID-19 pandemic.

Recently published meta-analysis in ICM produced conflicting results-

Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression

of randomized-controlled trials

A meta-analysis of RCTs with the use of tocilizumab in COVID-19. Studies were included if tocilizumab was compared with placebo or with standard care as the control arm. The authors initially screened 2175 reports through Boolean search, and finally identified 10 RCTs.

NIV was used in 7 trials, HFNO in 5, oxygen alone in 2. Nine trials used tocilizumab, one used sarilumab and one trial used either drug. The dose of tociluzimab was 8 mg/kg in 8 trials, with a repeat dose if there was no response, while one trial used 6 mg/kg. Four trials used placebo control while tocilizumab was compared to standard care in others.

Publication bias was observed, but this was only towards negative trials. The quality of evidence based on the GRADE criteria revealed that the studies were of moderate or very low quality.

Primary outcome

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%.

Secondary outcomes

Progression to mechanical ventilation (7 trials): 8.7 vs. 10.5%; 0.7 (CI: 0.54–0.89), P = 0.04

Progression to ICU (4 trials): no change between groups

Composite outcome of death, withdrawal from study, ICU care, or requirement for mechanical ventilation: 28.9 vs. 36.6%; OR: 0.7 (0.59–0.89), P = 0.002

Meta-regression: weak relation between tocilizumab treatment and the risk of mortality

Sensitivity analysis: trials with low risk of bias alone (5 trials): no change in mortality 12.3 vs. 10.7%

Limitations

• 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 was variable
• The RECOVERY trial suggested that the combination of corticosteroids and tocilizumab was effective, while tocilizumab alone may be ineffective
• The incidence of adverse events was very low, and may be underreported; hence, possible harm from tocilizumab remains unclear
• Most trials were open label, which may have resulted in a bias

Our recommendation – 

Tocilizumab shouldn’t be used routinely and in isolation.

Its use should be guided by surrogate markers of cytokine markers ( although this is not proven)

Patients should be monitored for long term outcomes including quality of life.

The mortality due to secondary bacterial or fungal infections post tocilizumab needs to be reported and published.