Higher dexamethasone dose of no benefit in critically ill COVID-19 patients

28th October 2021

Doubling the dose of dexamethasone dose in COVID-19 patients hospitalised with severe hypoxia had no effect on 28-day mortality.

Increasing the dexamethasone dose from 6 mg to 12 mg/day in hospitalised patients with COVID-19 and severe hypoxia, has no effect on overall mortality. This was the conclusion of a randomised trial undertaken by researchers from the COVID STEROID 2 Trial group, Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark. The value of dexamethasone in hospitalised patients with COVID-19 was shown in an open-label trial published in February 2021, which found that dexamethasone 6mg/daily for 10 days, resulted in a lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen. Guidance from the World Health Organisation also recommends a dexamethasone dose of 6 mg/daily either orally or intravenously.

Whether a higher dexamethasone dose would be more beneficial to those with severe COVID-19 is uncertain. However, some evidence suggests that in patients with acute respiratory distress syndrome (which can be induced by infection with the virus) initial dexamethasone doses of 20 mg for five days, could reduce the duration of mechanical ventilation and overall mortality. Thus, the purpose of the COVID STEROID 2 trial was to evaluate the efficacy and safety of a higher dose of dexamethasone in hospitalised adult patients with COVID-19 and severe hypoxia. The researcher’s working hypothesis was that a higher dexamethasone dose would increase the number of days alive without life support. The study was conducted at 26 hospitals in four countries and included patients who required supplemental oxygen, and both non-invasive and invasive mechanical ventilation. Participants were randomised 1:1 to receive either 6 or 12 mg of dexamethasone daily as a bolus injection for up to 10 days after randomisation. Patients were assessed after 28 days with the primary outcome set as the number of days alive without life support (i.e., invasive mechanical ventilation, circulatory support or kidney replacement therapy) after 28 days. There were several secondary outcomes, including the number of days alive without life support at 90 days.

Findings

A total of 982 randomised patients were included in the final analysis with a median age of 65 years (31% female). The most common co-morbidities were diabetes (27% in the 12 mg dexamethasone group, 34% in the 6 mg group) and ischaemic heart disease or heart failure (14% in both groups). After 28 days, the median number of days alive without life support was 22 days in those with a dexamethasone dose of 12 mg and 20.5 days in the dexamethasone 6 mg group (adjusted mean difference, aMD  = 1.3 days, p = 0.07). The 28-day mortality was 27.1% and 32.3% (dexamethasone 12 mg vs 6 mg). Similarly after 90 days the corresponding number of days was 84 and 80 days (dexamethasone 12 mg vs 6 mg) and this difference was not statistically significant.

The authors concluded that doubling the dexamethasone dose did not improve the number of days alive but suggested that they trial might have been underpowered to identify a significant difference.

Citation

The COVID STEROID 2 Trial Group. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomised Trial. JAMA 2021

Cardiopulmonary events not reduced in symptomatic outpatients with COVID-19

21st October 2021

Cardiopulmonary events were unaffected by antithrombotic therapy in symptomatic outpatients with COVID-19 but the trial was terminated early.

The level of cardiopulmonary events such as symptomatic deep vein thrombosis, pulmonary embolism, myocardial infarction and ischaemic stroke are not affected by the use of antithrombotic therapy. This was the conclusion of a randomised, double-blind, placebo-controlled trial among symptomatic outpatients infected with COVID-19 undertaken by a group from the Brigham and Women’s Hospital, Boston, Massachusetts, US. The risks of thromboembolic events in patients with covid-19 are high and associated with a greater risk of death. While there is some evidence indicating that the use of heparins among non-critically ill hospitalised patients with Covid-19 increases  the probability of survival, there is a paucity of data on the use of antithrombotic therapy among symptomatic outpatients.

The ACTIV-4B COVID-19 Outpatient Thrombosis Prevention Trial was designed to explore whether patients infected with COVID-19 but who were not sufficiently unwell to require hospitalisation, could benefit from anti-platelet or anticoagulant (i.e., antithrombotic) therapy, as a means of slowing disease progression. Patients aged between 40 and 80 years of age with a PCR or antigen confirmed diagnosis of COVID-19 were eligible for inclusion in the study. All were randomised in a 1:1:1:1 fashion to aspirin 81 mg daily (and matching placebo), apixaban 2.5 mg twice daily, apixaban 5 mg twice daily or placebo twice daily for a period of 45 days. The primary outcome of interest was a composite of cardiopulmonary outcomes including symptomatic deep vein thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, ischaemic stroke, hospitalisation for cardiovascular or pulmonary events and all-cause mortality, for up to 45 days.

Findings

In total, 657 patients with a median age of 54 years (59.1% women) were randomised to one of the four arms and the median time from diagnosis to randomisation was 7 days and 3 days between randomisation and the start of therapy. During this period of time, some patients were hospitalised and complete follow-up were available for only 556 individuals. Unfortunately, the incidence of cardiopulmonary events was low, with only 5 events; 1 deep vein thrombosis in the aspirin group, 3  cardiopulmonary events (all hospitalisations), 2 in the apixaban 5 mg group, 1 in apixaban 2.5 mg group) and one hospitalisation in the placebo group. While the event rate was very low, the authors also noted that there were no major bleeding events reported during the trial and there were no deaths. However, there were 4 suspected non-major bleeds in the aspirin group with 6 and 4 in the low and high apixaban groups respectively.

The authors reported that the trial was terminated early due to the low event rate. They concluded that while among clinically stable symptomatic outpatients, treatment with aspirin or apixaban did not reduce the rate of clinical outcomes. However, the generalisability of this conclusion is limited because of the low incidence of primary events.

Citation

Connors JM et al. Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19. The ACTIV-4B Randomized Clinical Trial. JAMA 2021

AZD7442 reduces risk of severe COVID-19 and death

19th October 2021

AZD7442, a long acting antibody combination, reduced the risk of severe illness and mortality in non-hospitalised patients with COVID-19.

AZD7442 is a long acting monoclonal antibody combination containing tixagevimab and cilgavimab which are derived from the B-cells donated by convalescent patients after infection with COVID-19. According to a press release from the manufacturer, Astra Zeneca, AZD7442, achieved a significant reduction in severe COVID-19 or death, compared to placebo in non-hospitalised patients with mild to moderate infection.

Efficacy

In august 2021, AstraZeneca announced that AZD7442 reduced the risk of developing COVID-19 by 77% compared to placebo. Now, the manufacturer has released preliminary results come from TACKLE which is a randomised, phase 3 trial, assessing the efficacy of a single 600mg IM dose of AZD7442 compared to placebo for the outpatient treatment of COVID-19. The study recruited adults (> 18 years of age) who were non-hospitalised, with PCR confirmed mild-to-moderate COVID-19 and  symptomatic for no more than seven days. Included in the trial were approximately 13% of adults aged 65 years and over 90% of participants had baseline co-morbidities or other characteristics putting them at a high risk of progression to more severe infection with COVID-19 such as  cancer, diabetes, obesity, chronic lung disease or asthma, cardiovascular disease or immunosuppression.

The participants were randomised in a 1:1 fashion to either AZD7442 (n = 452) or saline placebo (n = 451), administered in two separate sequential IM injections.The primary endpoint of the study was the composite of either severe COVID-19 or death from any cause through to day 29, although participants will continue to be followed for 15 months.The trial met the primary endpoint, reducing the risk of developing severe COVID-19 or death (from  all causes) by 50% compared to placebo, with 18 events in the AZD7442 arm and 37 in the placebo arm and AZD7442 was generally well tolerated in the trial. In addition, the company reports that in a pre-specified analysis among participants who received the combination  within five days of symptom onset, AZD7442 reduced the risk of developing severe COVID-19 or death (from any cause) by 67% compared to placebo, with nine events in the AZD7442 arm and 27 in the placebo arm (27/251).

AstraZeneca has already submitted data in the US, to the FDA to seek emergency Use Authorisation for AZD7442 for prophylaxis of COVID-19. AZFD7442 is also being studied as a potential treatment for patients hospitalised with COVID-19 as part of the ACTIV-3 trial.

Source. AstraZeneca press release.

Uncertainty over whether COVID-19 leads to ocular symptoms

6th January 2021

The fact that COVID-19 could be transmitted via the ocular route has prompted the use of protective eyewear. However, while reports in the literature describe ocular symptoms among infected individuals, whether these are due to COVID-19 remains unclear.

Several studies have suggested that COVID-19 can give rise to ocular symptoms but the causal relationship with the virus is uncertain and this prompted researchers from the Advanced Eye Centre, Department of Ophthalmology, Chandigarh, India, to perform a systemic review and meta-analysis of the eye problems documented in patients with COVID-19. They sought to document the range and frequency of reported eye problems in prospective and retrospective studies as well as case series in patients with a confirmed diagnosis of COVID-19, based on a positive PCR and appearing in any age group. The primary outcomes for the study included the proportion of patients with ocular involvement, ocular complications and the percentage of patients who first clinical manifestation of COVID-19 was ocular involvement.

Findings
An extensive search of the literature identified 222 citations although after removal of duplicates and screening of abstracts, only 16 articles met the inclusion criteria. The analysis revealed that overall, 11.6% of those with COVID-19 experienced an ocular problem. The most common problems were pain (31%), watering (15.3%) and dryness (13.3%). Other possible manifestations included follicular conjunctivitis (7%), conjunctival chemosis (4.4%), while ocular redness or conjunctival congestion affected an average 10.8% of patients. Only 2.2% of studies reported on how ocular problems occurred as the first symptom of infection. Interestingly, the authors found that in 6 of the studies for which data was collected on PCR testing from conjunctival swabs or tear samples, among 335 patients, COVID-19 was detectable in only 12 (3.5%) samples. This lead to authors to discuss how it remained unclear from the studies, whether the ocular symptoms reported by patient developed as a direct consequence of infection or if these were present beforehand. Moreover, given the low positivity rates in ocular samples, it would suggest that the potential risk from ocular transmission is likely to have been overestimated.

Citation
Aggarwal K et al. Ocular surface manifestations of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. PLoS ONE 2020 doi. org/10.1371/journal.pone.0241661