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21st October 2021
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.
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.
19th October 2021
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.
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.
Statin use appears to be associated with a lower mortality in those infected with COVID-19 according to the results of a large, Swedish cohort study. Previous studies in this area have been ambiguous. For example, a Danish observational study concluded that “recent statin exposure in patients with COVID-19 infection was not associated with an increased or decreased risk of all-cause mortality or severe infection.” In contrast, a US study observed a greater than 50% reduction in the risk of developing severe COVID-19 after controlling for co-morbidities and other treatments. Although a meta-analysis of studies on the use of statins and outcomes for COVID-19, concluded that the drug class was not associated with an improvement in a composite of poor outcomes, there was substantial heterogeneity with the included studies. While on-going trials examining the adjunctive value of statins will ultimately provide some much needed clarity of the possible benefit of this class of medicine, a team from the Department of Global Public Health, Karolinska Institute, Stockholm, Sweden, have published data from a large, population-based observational study, examining the relationship between statin use and COVID-19 mortality.
Using a prescribed drug registry, the team included individuals aged 45 years and older prescribed any type of statin between March 2019 and the end of February 2020. These individuals were followed-up until death from either COVID-19 or any other cause. For their study, the primary outcome of interest was death from COVID-19 and the analysis was presented as adjusted hazard ratios. Adjustments were made for numerous factors including age, gender, income, household crowding and wide range of co-morbidities.
A total of 963,876 individuals were included in the analysis. The cohort comprised, 169, 642 statin users with a median age of 71 years (43.4% female) with hypertension being the most common co-morbidity (74.3%). Overall, 2,545 individuals died from COVID-19 during the period of follow-up; 756 (0.5%) who were statin users, giving an adjusted hazard ratio for mortality of 0.88 (95% CI 0.79 – 0.97, p = 0.01) compared to non-statin users. This association did not differ by gender (p = 0.65), across age groups (p = 0.82) or COVID-19 risk groups (p = 0.72).
Although of course these data do not prove that statin use reduces death in those with COVID-19, it offers some tentative clues that individuals using these drugs appear less likely to die from infection with the virus. The authors concluded that the results provide some support for the continued use of statins during the COVID-19 pandemic.
Bergqvist R et al. HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden: A registry- based cohort study. PLoS Med 2021
6th January 2021
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.
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.
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