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Take a look at a selection of our recent media coverage:

Statin use linked to reduced hospitalisation and mortality risk from COVID-19

6th July 2022

Prior statin use resulted in a significantly lower risk of both hospitalisation and mortality among patients infected with COVID-19

Statin use as primary prevention against cardiovascular disease is associated with a significant reduction in the risk of hospitalisation and mortality among patients who become infected with COVID-19. This was the conclusion of a large, propensity-matched analysis of the French National Healthcare database by a team from the French National Agency for Medicines and Health Products Safety, Paris, France.

While the introduction of COVID-19 vaccines has significantly reduced both hospitalisation and mortality from COVID-19, prior to this drug repurposing was examined as a potential means for reducing the severity of infection and one class of drugs examined were the statins. There were good reasons to consider statins as potentially anti-viral agents because previous work had shown that in patients hospitalised with laboratory-confirmed seasonal influenza, statin treatment is associated with a 41% reduction in 30-day mortality. Moreover, other work found that cells treated with statins produced Ebola virus particles devoid of the surface glycoproteins required for virus infectivity.

There is already some evidence that among patients taking statins, there is a statistically significant decrease in the odds of in-hospital mortality in those with COVID-19. Nevertheless, this is not a consistent finding with other data has suggesting that the use of statins (in patients with type 2 diabetes) is associated with increased mortality among those hospitalised with COVID-19. Much of the research to date did not include a control group and for the present study, the French team identified patients aged 40 years and older, prescribed one of several statins (the exposed group) and propensity-matched these individuals based on age, gender, co-morbidities and sociodemographic factors (control group). But the team were also interested in whether there were differences between individual drugs within the class and if the intensity of therapy (e.g., low, moderate or high) impacted on either COVID-related hospitalisation or mortality. The primary outcome of the study was COVID-19-related hospitalisation and using Cox proportion hazard models, adjusted for several covariates e.g., age, gender, co-morbidities, the researchers calculated event rates between those using statins and the matched-control patients.

Statin use and COVID-19 hospitalisation

A total of 2,058249 patients with a mean age 68.7 years (46.6% male) taking statins were matched with the same of number of control patients. The most common co-morbidities were hypertension (41.8%) and diabetes (33.7%). There were a total of 9,396 hospitalisations for COVID-19, 4372 among those in the control group.

In fully adjusted models, patients in the statin group had a 16% lower risk of hospitalisation (hazard ratio, HR = 0.84, 95% CI 0.81 – 0.88, p < 0.0001). This relationship was maintained for the different agents within the class. For example, the risk was reduced by 25% for fluvastatin (HR = 0.75) and simvastatin (HR = 0.79). The relationship was also significant for low (e.g. fluvastatin 20/40 mg), medium (e.g., simvastatin 10 mg), not not for high (e.g., atorvastatin 40 or 80 mg) intensity therapy.

A similar reduction in risk was also evident for mortality among those taking statins (HR = 0.77, 95% CI 0.69 – 0.86). However, both atorvastatin and fluvastatin did not have a significant effect on mortality and as with hospitalisation, there was no significant effect for high intensity therapy on mortality.

The authors concluded that their data suggested a relatively small, but robust reduction in the risk of COVID-19-related hospitalisation and death among those prescribed statins before hospital admission.

Bouillon K et al. Association of Statins for Primary Prevention of Cardiovascular Diseases With Hospitalization for COVID‐19: A Nationwide Matched Population‐Based Cohort Study J Am Heart Assoc 2022

Paxlovid remains effective in those vaccinated against COVID-19

4th July 2022

Israeli researchers have found that paxlovid use in those at risk of COVID-19 progression remains effective even in fully vaccinated patients

The effectiveness of the anti-viral drug paxlovid in preventing the progression of COVID-19 remains even in those who have been adequately vaccinated against the virus according to the results of a real-world study by Israeli researchers.

Paxlovid consists of nirmatrelivir, a protease inhibitor against COVID-19 and ritonavir, which reduces the in vivo metabolism of nirmatrelivir. The published data for the drug (the EPIC-HR trial) suggested that treatment of symptomatic COVID-19 in patients at risk of progression to severe disease, results in an 89% lower risk compared to placebo. Nevertheless, the study was undertaken before omicron became the main circulating variant and therefore the generalisability of the study’s findings are potentially limited. Consequently, for the present study, the Israeli team decided to undertake a large, retrospective cohort study of high-risk COVID-19 patients, to assess the effectiveness of paxlovid at preventing progression to severe COVID-19 and subsequent death during the time when omicron was the predominant strain.

Using a large, national health service database, the researchers identified all adults (18 years and over) who tested positive for COVID-19 but restricted the search to those who would be suitable candidates for treatment with paxlovid, i.e., those who were older than 60 years, with a body mass index (BMI) greater than 30 and with co-morbidities including diabetes, hypertension and cardiovascular disease. However, unlike in the EPIC-HR trial, where those who had been vaccinated were excluded, for the present analysis, researchers included patients, regardless of their vaccination status. The main outcome of the study was a composite of severe COVID-19 or COVID-19-related mortality. For their analysis, the researchers included demographic and co-morbidity data and which were adjusted for in the analysis.

Paxlovid and progression of COVID-19

A total of 4,737 individuals with a mean age of 68.5 years (42.1% male) were treated with paxlovid and compared with 175,614 individuals who tested positive but who did not receive the drug. In total, 77.8% of those given paxlovid had adequate COVID-19 vaccination compared to 75% of those in the non-paxlovid group.

Overall, the primary outcome occurred in 39 individuals receiving paxlovid compared to 903 in those not given the drug. Paxlovid was therefore associated with a significantly lower risk of severe COVID-19 or mortality (hazard ratio, HR = 0.54, 95% CI 0.39 – 0.75). Moreover, among the whole cohort, having adequate COVID-19 vaccination, was also associated with a significantly lower risk of the primary outcome (HR = 0.20, 95% CI 0.17 – 0.22).

When the analysis was restricted to those diagnosed with COVID-19 when omicron was the main circulating variant, paxlovid was also associated with a greater reduction in the primary endpoint (HR = 0.43, 95% CI 0.64 – 0.85). Interestingly, among those given paxlovid and who were adequately vaccinated, there was still a significant reduction in the primary outcome (HR = 0.62, 95% CI 0.39 – 0.98) as well as among those not vaccinated (HR = 0.52, 95% CI 0.32 – 0.82).

The authors concluded that their study had demonstrated that in a real-world setting and during the period of time when omicron was the dominant variant, paxlovid was associated with a significant reduction in progression of COVID-19 and COVID-19-related mortality.

Najjar-Debbiny R et al. Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients Clin Infect Dis 2022

CT chest differences reveal less severe infection with omicron compared to delta

29th June 2022

CT chest changes are less severe with the omicron COVID-19 variant compared to delta and help explain the better patient outcomes with delta

Computed tomography (CT) chest scan changes after infection with the omicron COVID-19 variant are less severe than those seen with the delta variant and lead to better patient outcomes. This was the conclusion of an analysis of CT chest scans by researchers from Oxford University, UK.

The COVID-19 omicron variant of concern was first identified in South Africa in November 2021 and an analysis in January 2022 suggested a significantly reduced chance of being hospitalised for individuals infected with the omicron variant compared to previous variants of concern. In fact, the authors suggested that this reduction in severity was most likely due due to a degree of protection from prior immunity. While there is evidence to show that among those who experience a breakthrough COVID-19 infection, examination of CT chest scans indicate a lower level of pneumonia, the study did not provide any information on the infective variants involved. Moreover, a CT chest has become a valuable tool for the detection of both alternative diagnoses and complications of COVID-19, but to date, there is a lack of information on the CT changes induced after infection with different COVID-19 variants.

For the present study, the Oxford team compared the radiological patterns, imaging characteristics and disease severity on initial CT chest angiograms of patients infected with the omicron and delta variants of concern. They retrospectively collected data on patients hospitalised and with a PCR confirmed positive COVID-19 test, using the S gene target failure as a surrogate for omicron infections. For the CT chest scans, a severity score (CT-SS) was calculated (ranging from 0 to 25, with higher scores reflecting greater severity) and CT imaging features such as bronchial wall thickening were also assessed. Additional data collected included demographics, co-morbidities, laboratory findings, in-hospital treatments and clinical outcomes. Logistic regression models were created and adjusted for potential confounding variables to identify any differences in outcomes for the two variants.

CT Chest changes induced by omicron and delta variants

A total of 106 adult patients with a mean age of 58 years (55% male) were included in the final analysis, of whom, 66 were infected with the delta variant.

Based on the CT chest findings, a higher proportion of scans were categorised as normal in patients with omicron compared to delta (37% vs 15%, omicron vs delta, p = 0.016). Interestingly, only 40% of those infected with omicron compared to 83% of those with delta, displayed the typical signs of pneumonia.

Patients infected with omicron had a lower median CT-SS score compared to those with delta (3.5 vs 11.8). Furthermore, bronchial wall thickening was more common in those with omicron (odds ratio, OR = 2.4, 95% CI 1.01 – 5.92, p = 0.04).

Infection with the delta variant was also associated with a higher odds of more severe infection (OR = 4.6, 95% CI 1.2 – 26, p = 0.01) and critical care admission (OR = 7).

The authors concluded that infection with the omicron variant is associated with fewer and less severe changes on a CT chest compared to the delta variant and led to better patient outcomes.

Tsakok MT et al. Chest CT and Hospital Outcomes in Patients with Omicron Compared with Delta Variant SARS-CoV-2 Infection Radiology 2022

Single dose of Evusheld reduces progression of COVID-19 and mortality

24th June 2022

A single dose of Evusheld given intramuscularly to unvaccinated, patients with COVID-19 reduced both the need for hospitalisation and death, according to the TACKLE study

A single dose of Evusheld given to non-hospitalised, unvaccinated patients experiencing mild to moderate COVID-19 led to a significant reduction in progression to more severe disease (i.e., hospitalisation) and mortality compared to those given placebo. These were the key findings from the the TACKLE study by a group of UK and US researchers.

Evusheld contains the two monoclonal antibodies, tixagevimab and cilgavimab, which simultaneously bind to distinct, non-overlapping epitopes on the spike protein receptor binding domain and are therefore able to neutralise COVID-19. It is administered as a single intra-muscular dose and in March 2022, the EMA granted a marketing authorisation for Evusheld for the prevention of COVID-19 in adults and adolescents from 12 years of age weighing at least 40kg before potential exposure to the virus.

The combination of monoclonal antibodies has been examined in TACKLE, which is an ongoing, Phase III randomised, double-blind trial conducted in 95 sites across the USA, Latin America, Europe and Japan. Included patients are adults (18 years and over) with a documented, laboratory confirmed PCR or antigen test, COVID-19 infection, at least 3 days before enrolment in the trial. An additional entry requirement is a score of > 1 but less than 4 on the World Health Organization (WHO) Clinical progression Scale.

For the study, all eligible participants were randomised 1:1 to a single dose of Evusheld (600mg, which consists of two consecutive doses of 300mg of each) or saline solution (which served as the placebo) on the first day of the trial. The primary outcome of the study was a composite endpoint of either severe COVID-19, defined by either the presence of pneumonia, hypoxaemia plus a WHO scale score of 5 and higher or all-cause mortality.

Single dose of Evusheld and COVID-19 outcomes

A total of 903 participants with mean age of 46.1 years (50% female) were enrolled and randomised to evusheld (452) or placebo. Just over half (52%) of participants were of Hispanic or Latino ethnicity with 62% being White and 4% Black or African American. A total of 89% of the entire cohort had at least one or more risk factors for severe COVID-19 including a body mass index > 30 (43%), hypertension (28%), current smokers (40%) and diabetes (12%).

The primary endpoint (severe COVID-19 or death) occurred in 4% of those receiving a single dose of Evusheld and in 9% of those given a placebo and this difference was significant (absolute risk reduction = 4.5%, 95% CI 1.1 – 8.0, p < 0.0001).

In terms of safety, adverse effects occurred in 29% of those given Evusheld and 36% of those using placebo and most were deemed to be of mild or moderate severity.

The authors concluded that a single dose of Evusheld was associated with a statistical and clinically meaningful reduction in both progression to more severe COVID-19 and death compared with placebo among unvaccinated adult patients.

Montgomery H et al. Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial Lancet Respir Med 2022

Paxlovid of no benefit to low risk patients with COVID-19

21st June 2022

Paxlovid is of no benefit to patients at a low risk of either being hospitalised or death after infection with COVID-19

According to the results of a press release from the manufacturer, Pfizer, paxlovid does not benefit patients who are either unvaccinated or vaccinated and who are deemed not at a high risk of severe complications such as hospitalisation or death if infected with COVID-19.

Paxlovid is a protease inhibitor antiviral therapy against COVID-19 and was developed to be taken orally, at the first sign of infection or at first awareness of an exposure. The early use of the drug could therefore help patients avoid severe illness and which might lead to hospitalisation or death, or avoid disease development following contact with an infected individual.

The June 2022 press release, follows on from the success of the results from an earlier trial, EPIC-HR, in which symptomatic, unvaccinated, non-hospitalised adults, at high risk for progression to severe COVID-19, were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelivir plus 100 mg of ritonavir (i.e., Paxlovid) or placebo every 12 hours for 5 days.  The results of EPIC-HR were published in February 2022 and showed that treatment of symptomatic COVID-19 with paxlovid reduced the risk of progression to severe COVID-19 by 89% compared to placebo and without any major safety concerns. Based on these encouraging results, both the FDA and EMA approved the use of paxlovid for the treatment of mild-to-moderate COVID-19 in adults and children (12 years and older) who were deemed to be at high risk for progression to severe COVID-19, including hospitalisation or death.

With the success of their drug in high-risk patients, Pfizer proceeded with EPIC-SR, a phase 2/3 trial entitled, Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR). This time, the trial was designed to evaluate efficacy and safety in patients with a confirmed diagnosis of COVID-19 infection and who were deemed to be at standard risk (i.e., having a low risk for either hospitalisation or death). Enrolled participants were randomised 1:1, to receive paxlovid or matching placebo orally twice daily for five days.

Paxlovid in low-risk patients

The latest press release provides an updated analysis of the results from the EPIC-SR trial. The trial’s primary endpoint was self-reported, sustained alleviation of all (COVID-19) symptoms for four consecutive days. In an earlier press release from December 2021, Pfizer reported that primary endpoint in EPIC-SR was not met although this was based on an analysis of only 45% of the trial’s planned enrolment. Based on an updated analysis of 1,153 patients enrolled through December 2021, the current press release re-affirms, the results of the earlier, interim analysis. The data show that there was a non-significant 51% relative risk reduction in the primary outcome and in a sub-group analysis of 721 vaccinated adults who had at least one risk factor for progression to severe COVID-19, there was also a 57% non-significant relative risk reduction in hospitalisation or death.

However, not all of the current data is negative. When performing an additional analysis of secondary endpoint data, treatment with Paxlovid resulted in a nominally significant 62% decrease in COVID-19-related medical visits per day across all patients, relative to placebo (p = 0.0228).

Following these results, the press release reports that Pfizer has decided to cease enrolment into EPIC-SR due to low rate of hospitalisation or death in the standard-risk population but will continue to evaluate treatment in populations with high unmet need.

Clinical benefits of molnupiravir may extend beyond hospitalisation and death

17th June 2022

A further analysis of trial data suggests additional clinical benefits of molnupiravir in the treatment of patients infected with COVID-19

The clinical benefits of molnupiravir may not just be restricted to a reduction in either hospitalisation or death, according to the results of a secondary analysis of data from the MOVe-OUT trial by an international group of researchers in collaboration with the manufacturer, Merck and Co.

Molnupiravir is a small-molecule ribonucleoside prodrug of N-hydroxycytidine (NHC) and was studied in MOVe-OUT a phase 3, double-blind, randomised, placebo-controlled trial. The aim of the trial was to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in non-hospitalised, unvaccinated adults with mild-to-moderate, COVID-19 and at least one risk factor for severe COVID-19 illness. The findings of the study indicated that the drug, given at a dose of 800 mg every 12 hours for 5 days, was able to reduce the risk of hospitalisation or death when given within 5 days of the onset of COVID-19 symptoms.

While molnupiravir was clearly effective, researchers wondered if there were any further clinical benefits attributable to the drug and therefore decided to perform a secondary analysis of data generated in the trial. In particular, the researchers focused on the need for respiratory interventions, COVID-19-related acute care visits and changes in the level of inflammatory markers such as C-reactive protein (CRP). The reported outcomes were assessed in terms of the relative risk reduction (RRR).

Additional clinical benefits of molnupiravir

The trial randomised 1433 participants to either molnupiravir or placebo. A reduction in CRP levels was noted as early as day 3 and this was greater than for the placebo group (-1.44 vs 1.92, molnupiravir vs placebo, p value not stated) and in fact, CRP levels in the placebo group did not reduce until day 10.

Fewer patients given molnupiravir required any respiratory interventions (RRR = 34.3%, 95% CI 4.3% – 54.9%), in particular noninvasive mechanical ventilation (RRR = 75.4%). In addition, among the subgroup of patients who became hospitalised, fewer treated with molnupiravir required any form of respiratory intervention (RRR = 21.3%).

There was also difference in the proportion of molnupiravir patients requiring either an acute care visit (RRR = 32.1%) or a COVID-19-related acute care visit (RRR = 33.8%) compared to those taking placebo.

While there were apparent improvements in numerical changes in CRP values, the authors did not report the associated statistics for the change and it is therefore unclear whether the observed differences between the outcomes examined were statistically significant. It is also unclear if these differences were clinically meaningful. A further limitation recognised by the authors was that the data were derived from patients who were unvaccinated against COVID-19 and so the generalisability of the findings to patients already vaccinated are not clear.

Despite these limitations, the authors concluded that their findings suggested added clinical benefits from the use of molnupiravir in the treatment of non-hospitalised adults with mild to moderate COVID-19.

Johnson MG et al. Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19. A Randomized, Placebo-Controlled Trial Ann Intern Med 2022

Study finds vitamin D status and COVID-19 diagnosis shows inconsistent associations

14th June 2022

A large study revealed no consistent associations between vitamin D status and COVID-19 outcomes such as infection, hospitalisation and death

There are inconsistent associations between vitamin D status and the diagnosis of COVID-19, hospitalisations and mortality according to the findings of a large cohort study by researchers from Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Vitamin D is essential for bone health such that prolonged and severe vitamin D deficiency gives rise to rickets in children and osteomalacia in adults. Furthermore, vitamin D is an immune system modulator that induces an increase in antimicrobial proteins and activity against pathogens. In a systemic review of studies, it was found that supplementation with vitamin D results in a small reduction in the risk of acute respiratory infections although the role of vitamin D in COVID-19 remains uncertain. In a 2021 Cochrane review, the authors concluded that there is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. But if vitamin D status and in particular, a deficiency of the vitamin, is associated with COVID-19, the use of supplements could be a valuable health intervention. As a result, for the present study, the UK team set out to examine the association between vitamin D status and several COVID-19 outcomes including infection, hospitalisation and death. They used data held within the UK Biobank and included individuals for whom at least one serum vitamin D test was available. Levels were recorded as deficient (< 25 nmol/L), insufficient (25 – 49 nmol/L) and sufficient ( > 50 nmol/L) and the primary outcome of interest was a laboratory confirmed infection with COVID-19. For their secondary outcomes, the team examined hospitalisation and mortality due to infection with the virus. The team also considered the risk of being diagnosed with COVID-19 when the vitamin D status was assessed, i.e., during the summer and winter months and used the definition of vitamin D sufficiency as the reference point. The analysis was performed using logistic regression after adjustment for covariates which included demographics, body mass index, smoking status and ethnicity.

Vitamin D status and COVID-19 outcomes

A total of 307, 512 individuals were included in the analysis of whom, 46% were deemed to vitamin D sufficient, 41% insufficient and 12% deficient. A total of 10,165 people became infected with COVID-19 with 51.4% of infections reported during autumn, 31% in the winter and only 3.8% in the summer.

Interestingly, during the summer months, participants who were vitamin D deficient had a 14% lower risk of being diagnosed with COVID-19 compared to those who were vitamin D sufficient (Hazard ratio, HR = 0.86, 95% CI 0.77 – 0.95, p < 0.01). In contrast, during the non-summertime months, the risk of becoming infected with COVID-19 was 14% higher among those who were vitamin D deficient (HR = 1.14, 95% CI 1.01 – 1.30, p = 0.04). However, there were no significant associations for individuals deemed vitamin D insufficient irrespective of the time of year.

With respect to COVID-19-related hospitalisations, compared to those who were vitamin D sufficient, there was no evidence that any other vitamin D status significantly affected the risk. Similarly, there was no evidence that the risk of COVID-19 mortality was affected by vitamin D levels.

In their conclusion the authors reported that there were inconsistent associations between vitamin D status and a diagnosis of COVID-19 and no clear association between vitamin D levels and either hospitalisation or death.

Lin LY et al. The association between vitamin D status and COVID-19 in England: A cohort study using UK Biobank PLoS One 2022

Hormone replacement therapy use linked to lower mortality risk from COVID-19

7th June 2022

Use of hormone replacement therapy within 6 months of an infection with COVID-19 is associated with a reduced mortality risk

The use of hormone replacement therapy (HRT) by women within 6 months of developing an infection with COVID-19 has been found to be linked with a significantly reduced risk of subsequent death, according to a retrospective analysis by a group of UK researchers.

Deaths from COVID-19 have shown a male bias with one estimate suggesting that men are 1.7-times more likely to die than women. However, this observation is not new and similar findings were observed with severe acute respiratory syndrome, where the mortality rate was 21.9% for men but only 13.2% for women. The reasons behind these apparent sex-related differences are unclear but attention has focused on a potentially protective effect of oestrogens. Data from the COVID symptom study found that women using the combined oral contraceptive pill had a lower rate of predicted infection with COVID-19 although the relationship with the use of hormone replacement therapy was less clear. To date, only one retrospective analysis of women using hormone replacement therapy has been undertaken and suggested that the fatality risk for women over 50 years of age and in receipt of oestradiol therapy was reduced by more than 50%.

In an effort to better understand the relationship between HRT use and mortality after infection with COVID-19, the UK team retrospectively examined information held in the Oxford-Royal College of General Practitioners Research and Surveillance Central database. They identified a cohort of women with a PCR confirmed COVID-19 infection and who had been prescribed HRT within 6 months of their date of infection. The researchers set the study’s primary outcome as all-cause mortality during the follow-up period (January 2020 to June 2020) and also extracted included age, ethnicity and co-morbidities which were adjusted for in their regression analysis.

HRT use and all-cause mortality

A total of 5451 women with a mean age of 59 years were included and followed for a mean of 164.9 days and of whom 4.3% were prescribed HRT.

As in other studies, the risk of death was higher among women who were older, underweight and with co-morbidities such as hypertension and the use of immunosuppressants.

During the follow-up period, a total of 664 women (12.2%) died and the risk of all-cause mortality was significantly less likely in those using HRT (odds ratio, OR = 0.22, 95% 0.05 – 0.94, p = 0.041). Interestingly, women prescribed HRT and asthma, had a much lower risk of mortality (OR = 0.58, 95% CI 0.42 – 0.81, p = 0.001) and the authors suggested that since these women were also likely to be prescribed steroids, this could have produced an added protective effect.

The authors concluded that women should be reassured that there was no reason to stop using HRT because of the pandemic and called for future studies to examine the effect of different doses and formulations and how these might impact on COVID-19 outcomes.

Dambha-Miller H et al. Mortality in COVID-19 among women on hormone replacement therapy: a retrospective cohort study Fam Pract 2022

Vasopressor use in critically ill COVID-19 patients associated with higher mortality

1st June 2022

Vasopressor use in patients with COVID-19 admitted to an intensive care unit due to critical illness increases the risk of mortality

Vasopressor use in COVID-19 patients who become critically ill is linked to an increased risk of death compared to those not given such drugs according to the results of a meta-analysis by a team of Greek and US researchers.

Patients who are critically ill with not only COVID-19 but any illness, require haemodynamic support. In 2020, the Surviving Sepsis Campaign COVID-19 panel issued a number of statements regarding the management of COVID-19. In relation to COVID-19 and shock, the panel advocated that for adults who experience shock, use of norepinephrine should be used as the first-line vasoactive agent. Vasopressor use is designed to increase vascular tone and is necessary in critically ill patients with profound haemodynamic impairment such that tissue blood flow is not sufficient to meet metabolic requirements. Vasopressors are commonly used, in fact, one survey of critical care staff managing patients with COVID-19 found that overall, 56% reported (combined very frequent/frequent use) vasopressor use in COVID-19 patients. Despite the impact on haemodynamic stability, vasopressors are known to have several adverse cardiovascular effects. For example, in one study, new-onset tachyarrhythmias, prolonged elevation of heart rate and myocardial cell damage were frequently observed and that overall, adverse cardiac events occurred in 48.2 % of all intensive care patients. Although current guidelines recommend the use of catecholamines for their haemodynamic effects, these drugs have numerous other biological effects in shock states including aggravation of hyper-metabolism by promoting hyperglycaemia, which further increase oxygen demands and can contribute to further organ damage. It is possible therefore that vasopressor use in critically ill COVID-19 patients could have a deleterious effect although this has not been fully examined.

For the present study (which is available as a preprint), the researchers systematically reviewed the literature for studies in which adult critically ill patients were given vasopressors. They set the primary outcome of interest as all-cause mortality at days 28 or 30 but if this data was missing, simply referred to the level of all-cause mortality reported. A secondary outcome considered was the level of acute kidney injury.

Vasopressor use and all-cause mortality

A total of 33 observational studies were included in the final analysis although only 30 included a direct comparison of vasopressor use vs no use. The remaining three studies examined either use of angiotensin-II use only (1 study) or angiotensin-II vs vasopressor use.

The primary outcome could be assessed from 21 of the studies with 7,900 patients. The analysis revealed that vasopressor use was associated with a statistically significant increased risk of mortality (relative risk, RR = 4.26, 95% CI 3.15 – 5.76,p < 0.001). In subgroup analysis by department of admission, i.e., intensive care (RR = 3.45) or high dependency unit (RR = 6.25) also revealed a significant increased mortality risk (p < 0.001 in both cases).

For the secondary outcome of acute kidney injury, vasopressor use was also significantly associated with a greater risk of the outcome (RR = 3.17, 95% CI 2.21 – 4.54, p < 0.001).

The authors concluded that vasopressor use was associated with a higher level of mortality in critically ill COVID-19 patients and called for further studies to estimate the correlation of specific vasopressor agents with adverse effects and mortality.

Mermiri M et al. The effect of vasopressors on mortality in critically ill patients with COVID-19: A systematic review and meta-analysis Med Rxiv 2022

Fourth COVID-19 vaccination effectiveness drops after 10 weeks

30th May 2022

A fourth COVID-19 vaccination’s effectiveness against infection drops after only 10 weeks but remains high against severe disease

A fourth COVID-19 vaccination dose offers greater protection against infection than three doses but this effectiveness quickly wanes within 10 weeks but is maintained against more severe disease. This was the key finding of a retrospective analysis by Israeli researchers.

The use of a third COVID-19 vaccination is more effective at protecting individuals against severe COVID-19-related outcomes in comparison to only two doses. Nevertheless, it is also becoming clear that in the presence of COVID-19 variants such as Omicron, the relative protection against infection even from three doses wanes over time. For instance, in one study, the effectiveness of a third COVID-19 vaccine, waned from 53.4% a month after vaccination to 16.5% three months later.

As a result, many countries are considering the use of a fourth dose although currently, the impact of a fourth COVID-19 vaccination on breakthrough infections and protection against severe infection is largely unknown, especially among the older and more vulnerable patients.

Due to this uncertainty, the Israeli team set out to compare the effectiveness of a fourth and third dose against infection and severe disease. They retrospectively analysed information held within a centralised healthcare national database and focused on patients over 60 years of age and examined a 10 week period between January to March 2022, starting 7 days after the date when the fourth COVID-19 vaccination could be administered to eligible patients. The main outcomes of interest were breakthrough infections, defined as occurring 7 or more days after vaccination and breakthrough infections that resulted in either hospitalisation or COVID-19-related death.

Fourth COVID-19 vaccination and breakthrough infections

A total of 97,499 individuals with a mean age of 70.8 years (45.3% male) were included, 69,623 of whom had received only three COVID-19 vaccinations.

The relative vaccine effectiveness of the fourth dose compared to the third dose peaked at 65.1% (95% CI 63 – 67.1%) three weeks after inoculation. However, this waned quickly, so that after 9 weeks, the effectiveness had reduced to 22% (95% CI 4.9 – 36.1%).

With respect to hospitalisation and deaths, the vaccine effectiveness peaked at 86.5% (95% CI 63.4 – 95%) 49 – 69 days after inoculation and was maintained over the 10 week period of analysis.

The researchers concluded that a fourth vaccine dose offered a higher level of protection against infection than three doses but that this protect waned over the following10 weeks. Nonetheless, protection against more severe disease was sustained over this period.

Gaxit S et al. Short term, relative effectiveness of four doses versus three doses of BNT162b2 vaccine in people aged 60 years and older in Israel: retrospective, test negative, case-control study BMJ 2022