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13th January 2022
Atorvastatin given to patients infected with COVID-19 and admitted to an intensive care unit (ICU) is not associated with a significant reduction in adverse outcomes according to research by a team from the Rajaie Cardiovascular Medical and Research Centre, Tehran, Iran.
Hydroxymethylglutaryl coenzyme A reductase inhibitors (or statins), are known to exert a direct antithrombotic effect in models of arterial and venous thrombosis via a mechanism unrelated to the cholesterol-lowering activity, as well as having anti-inflammatory properties. Furthermore, a 2021 systematic review also identified additional pleiotropic effects including antiviral and immunomodulatory that might help treat COVID-19.
Given this potential beneficial role for statins, the Iranian team sought to examine the impact of atorvastatin on thromboembolic events or death, in patients with the COVID-19, admitted to ICU. Their study was part of the INSPIRATION trial which had two arms: one that explored the effect of prophylactic anticoagulation and the other focusing on the use of atorvastatin.
The team recruited adult patients (> 18 years of age) with a PCR confirmed COVID-19 infection, admitted to ICU and in whom there was no baseline therapeutic need for a statin. Enrolled patients were then randomised 1:1 to atorvastatin 20 mg daily or matching placebo and followed for 30 days after randomisation. For patients requiring mechanical ventilation, the drug was delivered via a nasogastric or orogastric tube. The primary outcome of interest was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation or all-cause mortality within 30 days of randomisation.
A total of 587 patients with a median age of 57 years (44% female) were randomised to atorvastatin or placebo and treatment was used for a median of 21 days and slightly less, at 19 days for placebo. The median length of stay within ICU was 5 days in both groups.
After 30 days, the primary outcome had occurred in 95 (33%) of patients assigned to atorvastatin and 108 (36%) of those given placebo (odds ratio, OR = 0.84, 95% CI 0.58 – 1.21, p = 0.35). The results for the primary outcome were largely driven by mortality, with 31% and 35% of deaths in the atorvastatin and placebo groups respectively although no patients required extracorporeal membrane oxygenation.
The use of imaging tests such as computed tomography pulmonary angiograms and doppler, revealed a similar level of venous thromboembolism diagnoses in the two groups (20% vs 20%, p = 0.64). There was also no difference in the incidence of arterial thrombosis. In subgroup analysis, there were no sex-related differences, among patients older/younger than 65 years, smokers or in those with/without obesity or diabetes.
In trying to account for their findings, the authors speculated that atorvastatin may have had a small protective effect which was undetectable or that statins were only of benefit in the early stages of COVID-19 infection prior to the inflammatory response which led to irreversible damage.
INSPIRATION-S investigators. Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial. BMJ 2022
11th January 2022
Immunosuppressive biologics are not associated with an increased risk of either infection with COVID-19 or a higher incidence of death according to the findings from a team from the Department of Dermatology, Massachusetts General Hospital, Boston, US.
Whether immunosuppressive biologics would heighten the risk of infection with COVID-19 seems, at least from some evidence, to be unfounded. Despite this, other work has revealed an increased risk of mortality among patients with rheumatic diseases prescribed non-biologic immunosuppressants such as azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus.
With a potential risk for viral reactivation of an underlying chronic viral infection during immunosuppressive therapy, some have questioned whether patients with psoriasis, for example, should be started on immunosuppressive biologics.
In the present analysis, the US team focused on adult patients (18 years and over) and given at least one prescription for a biologic between July 2019 and February 2020 at their hospital. They undertook a retrospective, matched cohort study and set the primary outcome as the risk of COVID-19 infection and the secondary outcome as subsequent mortality. Using multivariable logistic regression, they calculated the odds ratio (OR) for a COVID-19 diagnosis between those prescribed immunosuppressant biologics and the control group and examined other potential factors associated with either infection or mortality.
A total of 7361 patients receiving immunosuppressant biologics were matched with 74,910 controls. The most common biologic agents were tumour necrosis factor inhibitors including adalimumab (28.4%), infliximab (15.6%) and etanercept (11.9%), CD20-directed antibodies including rituximab (15.6%) and interleukin-4A inhibitors such as dupilumab (8.6%).
Among the 7361 patients, the primary indication for the immunosuppressive biologics were mainly dermatological diseases such as psoriasis (27.3%) and atopic dermatitis (27.5%), although patients also received these drugs for rheumatoid arthritis (27.5%) and asthma (19.4%).
After adjustment for demographics and co-morbidities, overall, biologics were not associated with COVID-19 (OR = 0.88, 95% CI 0.71-1.09, p = 0.25). Patients prescribed tumour necrosis factor inhibitors were less likely to be diagnosed with COVID-19 compared to matched controls (OR = 0.69, 95% CI 0.48 – 0.98, p = 0.05). Similarly, those treated with dupilumab also had lower risk of being diagnosed, but this difference was non-significant (OR = 0.38, 95% CI 0.12 – 1.18, p = 0.10).
For the secondary outcome of mortality, after adjustment, the difference in rates between the those taking immunosuppressive biologics and controls were non-significant (OR = 1.13, 95% CI 0.57 – 2.76, p = 0.57).
In their regression analysis, the odds of mortality was significantly associated only with age (OR = 1.06, 95% CI 1.04 – 1.09, p < 0.001) with female patients having a much lower odds of mortality (OR = 0.53, 95% CI 0.34 – 0.83, p < 0.01).
They concluded that dermatologists and patients should prioritise the recognised risk factors for infection when making therapy decisions, given how immunosuppressive biologics do not appear to be a risk factor for either infection or mortality.
Pahalyants V et al. Immunosuppressive biologics did not increase the risk of COVID-19 or subsequent mortality: A retrospective matched cohort study from Massachusetts J Am Acad Dermatol 2021
2nd December 2021
Inhibition of the renin-angiotensin-aldosterone system (RAAS inhibition) reduces mortality in those hospitalised with COVID-19 and admitted to an intensive care unit. This was the finding of a retrospective analysis presented at the American Heart Association (AHA) conference 2021.
Inhibition of the RAAS system can be achieved through the use of both angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Although it has become widely accepted that the COVID-19 virus gains entry to cells via the angiotensin converting enzyme 2 receptor, whether existing use of drugs affecting the RAAS system affects the outcomes of those with more severe COVID-19 infection remains uncertain.
For the present study, researchers turned to the COVID-19 Critical Care Consortium which represents a global database of de-identified information on treatment outcomes of critically ill COVID-19 patients. The critical care consortium includes data from 354 centres in 54 countries and thus represents an important source of information for researchers as it generates a huge amount of clinical insight about the virus. The stated aim of the study was to examine the role of ACEi / ARB drug exposure (i.e., RAAS inhibition) on outcomes in COVID-19 patients with prior hypertension (HTN) and who had been admitted to intensive care units (ICU) due to the severity of their infection. For the analysis, researchers focused on adult patients (i.e., >18 years of age) and with pre-existing HTN. Outcomes of interest included the length of stay and in-hospital mortality to 90 days post ICU admission.
A total of 663 eligible patients were included in the analysis, of whom, 480 patients, with a median age of 65 years (67% male) had been prescribed an ACEi and / or ARB therapy in the 2 weeks before ICU admission. The average lengths of stays in both ICU and a general ward were longer in those prescribed ACEi / ARB drugs compared to non-users (20.8 days and 6.5 days vs. 15.5 and 6.0 days, respectively). However, RAAS inhibition treatment was associated with a decreased risk of death (Hazard ratio, HR = 0.69, 95% CI 0.54 — 0.88) which persisted after adjusting for propensity scores (HR = 0.67, 95% CI 0.53 — 0.86).
Based on these findings, the authors concluded that the use of ACEi/ARB’s for the management of pre-existing hypertension was associated with a reduced mortality risk in those admitted to an ICU after admission to hospital due to the severity of their COVID-19 infection.
Sato K et al. Abstract 10482: Renin-Angiotensin-Aldosterone System Inhibition is Associated with Reduced In-Hospital Mortality in Critically Ill Covid-19 Patients with Pre-Existing Hypertension. Circulation 2021
19th October 2021
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
29th July 2021
Patients with mental health problems might be at a greater risk of worse outcomes when infected with COVID-19, especially as such patients often have other co-morbidities, some of which have been identified as risk factors. In addition, mental health problems are associated with low socioeconomic status and which has been linked to a greater risk of critical care admission among those infected with COVID-19. In fact, data collected from several countries has already revealed how severe mental illnesses such as schizophrenia, are a risk factor for greater COVID-19 mortality although other work has concluded that a diagnosis of mental illness was not associated with an increased likelihood of testing positive for COVID-19. While a recent meta-analysis has suggested a pre-diagnosis of mental disorders worsens the prognosis of COVID-19, the analysis had methodological issues and did not examine the effect for individual diagnoses. This led a team from the CEReSS-Health Service Research and Quality of Life Centre, Marseille, France, to undertake a systematic review and meta-analysis of the accumulating evidence on mental health disorders and COVID-19. Their primary objective was simple to determine whether patients with mental health disorders were at an increased risk of COVID-19 mortality compared to those without such problems. A secondary objective was to explore if the presence of a mental health disorder increased the risk of intensive care admission and if there were any mental health conditions that specifically increased the risk of COVID-19 mortality. The team searched for articles which included participants with a diagnosis of a mental health disorder and a clinical diagnosis of COVID-19 and where intensive care unit and mortality data were included. Adjustments were made for the presence of other known risk factors for COVID-19, i.e., co-morbidities, age etc.
A total of 16 population-based cohort studies across seven countries with 19,086 patients were included in the meta-analysis. Overall, the present of mental health disorders was associated with an increased risk of COVID-19 mortality (odds ratio, OR = 1.38, 95% CI 1.15–1.65). In studies where only severe mental illness such as schizophrenia or bipolar disorder were included, the mortality risk was higher (OR = 1.67, 95% CI 1.02–2.73). There was no apparent association between any specific mental health disorder and COVID-19 mortality and there was insufficient data to determine whether mental health disorders were associated with intensive care admission.
Commenting on these findings, the authors suggested that individuals with mental health disorders should be targeted as a high-risk population for severe COVID-19, requiring enhanced disease management strategies. They concluded by calling for future studies to examine the risks associated with individual mental health disorders and to confirm their findings of the link between severe mental health and increased COVID-19 mortality.
Fond G et al. Association Between Mental Health Disorders and Mortality Among Patients With COVID-19 in 7 Countries. A Systematic Review and Meta-analysis. JAMA Psychiatry 2021