scholarly journals Clinical characteristics and outcomes of critically ill mechanically ventilated COVID-19 patients receiving interleukin-6 receptor antagonists and corticosteroid therapy: a preliminary report from a multinational registry

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Marwa Amer ◽  
Ahmed M. Kamel ◽  
Mohammed Bawazeer ◽  
Khalid Maghrabi ◽  
Abid Butt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Critically Ill ◽  
Interleukin 6 ◽  
Preliminary Report ◽  
Clinical Characteristics ◽  
Dose Range ◽  
Prescribing Patterns ◽  
High Dose ◽  
Receptor Antagonists ◽  
Interleukin 6 Receptor

Abstract Background Interleukin-6 receptor antagonists (IL-6RAs) and steroids are emerging immunomodulatory therapies for severe and critical coronavirus disease (COVID-19). In this preliminary report, we aim to describe the epidemiology, clinical characteristics, and outcomes of adult critically ill COVID-19 patients, requiring invasive mechanical ventilation (iMV), and receiving IL-6RA and steroids therapy over the last 11 months. Materials and methods International, multicenter, cohort study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Data were collected between March 01, 2020, and January 10, 2021. Results Of 860 patients who met eligibility criteria, 589 received steroids, 170 IL-6RAs, and 101 combinations. Patients who received IL-6RAs were younger (median age of 57.5 years vs. 61.1 and 61.8 years in the steroids and combination groups, respectively). The median C-reactive protein level was > 75 mg/L, indicating a hyperinflammatory phenotype. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (interquartile range: 6–14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. Of the patients who received IL-6RAs, the majority received one dose of tocilizumab and sarilumab (dose range of 600–800 mg for tocilizumab and 200–400 mg for sarilumab). Regarding the timing of administration, we observed that steroid and IL-6RA administration on day 0 of ICU admission was only 55.6% and 39.5%, respectively. By day 28, when compared with steroid use alone, IL-6RA use was associated with an adjusted incidence rate ratio (aIRR) of 1.12 (95% confidence interval [CI] 0.88, 1.4) for ventilator-free days, while combination therapy was associated with an aIRR of 0.83 (95% CI 0.6, 1.14). IL-6RA use was associated with an adjusted odds ratio (aOR) of 0.68 (95% CI 0.44, 1.07) for the 28-day mortality rate, while combination therapy was associated with an aOR of 1.07 (95% CI 0.67, 1.70). Liver dysfunction was higher in IL-6RA group (p = 0.04), while the bacteremia rate did not differ among groups. Conclusions Discordance was observed between the registry utilization patterns (i.e., timing of steroids and IL-6RA administration) and new evidence from the recent randomized controlled trials and guideline recommendations. These data will help us to identify areas of improvement in prescribing patterns and enhance our understanding of IL-6RA safety with different steroid regimens. Further studies are needed to evaluate the drivers of hospital-level variation and their impact on clinical outcomes. Trial registration ClinicalTrials.gov: NCT04486521. Registered on July 2020

scholarly journals Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 - Preliminary report

2021 ◽  
Author(s):  
◽  
Anthony C Gordon
Keyword(s):  
Intensive Care ◽  
Hospital Mortality ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Interleukin 6 ◽  
Ordinal Scale ◽  
Organ Support ◽  
Intensive Care Treatment ◽  
Receptor Antagonists ◽  
Interleukin 6 Receptor

Background: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. Methods: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility. Results: Tocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] -1, 16), 11 (IQR 0, 16) and 0 (IQR -1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists. Conclusions: In critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival.

scholarly journals Clinical Characteristics and Outcomes of Critically ill Mechanically Ventilated COVID-19 Patients Receiving interleukin-6 Receptor Antagonists and/or Corticosteroid Therapy, the INTERACT study: A Multicenter International Observational Study

2021 ◽  
Author(s):  
Marwa Amer ◽  
Mohammed Bawazeer ◽  
Khalid Maghrabi ◽  
Ahmed Mohamed Kamal ◽  
Abid Butt ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Combination Therapy ◽  
Observational Study ◽  
Clinical Characteristics ◽  
Low Dose ◽  
High Dose ◽  
Icu Patients ◽  
Mechanically Ventilated ◽  
Significant Difference ◽  
Interleukin 6 Receptor

AbstractObjectivesTo compare the clinical characteristics and outcomes of critically ill coronavirus disease (COVID-19) patients requiring mechanical ventilation (MV), receiving interleukin-6 receptor (IL-6R) antagonists, steroids, or a combination of both.DesignAn international, multicenter, observational study derived from the COVID-2019 Viral Infection and Respiratory Illness University Study (VIRUS) registry and conducted through the Discovery Network, the Society of Critical Care Medicine. Marginal structural modeling was used to adjust for time-dependent confounders, and observations were weighted using the inverse probability of treatment weight. Sensitivity analysis was conducted to emulate a target trial design.Setting168 hospitals in 16 countries.Patientsadult ICU patients (≥ 18 years) requiring MV for COVID-19 between March 01, 2020, and January 10, 2021.InterventionNone.Measurements and Main ResultsA total of 860 patients met eligibility criteria: 589 received steroids, 170 IL-6R antagonists, and 101 combination therapy, and the groups were balanced after adjustment. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (IQR: 6–14 mg); 80.8% received low-dose and 19.2% high-dose steroids (> 15 mg/day of dexamethasone or equivalent). The median C-reactive protein level was > 75 mg/L in majority of our cohort. The use of IL-6R antagonists alone or in combination was not associated with a significant difference in ventilator-free days (VFD) compared to steroids alone (adjusted incidence rate ratio [95% CI]): IL-6R antagonists (1.12 [0.88,1.4]), combination (0.83 [0.6,1.14]). Patients treated with low or high-dose steroids had non-significant differences in VFD compared to IL-6R antagonists (ß= 0.62, 95% CI −1.54, 2.78 for low-dose steroid; ß= −1.19, 95% CI −3.85, 1.47 for high-dose steroid). The use of IL-6R antagonists alone or in combination was not associated with a significant difference in 28-day mortality compared to steroids alone (adjusted odds ratio [95% CI]): IL-6R antagonists alone (0.68 [0.44,1.07]), combination (1.07 [0.67,1.7]). There was no difference in hospital mortality compared to steroids alone (aOR 0.68, 95% CI 0.43,1.09 for IL6-R antagonist, aOR 1.23, 95 % CI 0.72,2.11 for combination). The findings of sensitivity analysis were consistent with the primary analysis. The rate of liver dysfunction was higher in the IL-6R antagonist (p=0.038), while the rate of bacteremia did not differ among the three groups.ConclusionsWe observed no difference in outcomes between mechanically ventilated adult ICU patients who received IL-6R antagonists, steroids, or combination therapy and those who received IL-6R antagonists or low- or high-dose steroids. Further trials are needed to evaluate high-dose steroids as substitutes for IL-6R antagonists in resource-limited settings.

scholarly journals Assessment of anti-factor Xa activity in critically ill COVID-19 patients receiving three different anticoagulation regimens

2021 ◽  
Vol 9 ◽  
pp. 205031212110499
Author(s):  
Mohammed A Hamad ◽  
Shereen A Dasuqi ◽  
Aamer Aleem ◽  
Rasha A Omran ◽  
Rakan M AlQahtani ◽  
...  
Keyword(s):  
Critically Ill ◽  
Interleukin 6 ◽  
Factor Xa ◽  
Clinical Decision ◽  
Target Range ◽  
High Dose ◽  
Cytokine Storm ◽  
Heparin Infusion ◽  
Increased Risk ◽  
Therapeutic Doses

Introduction: Critically ill COVID-19 patients are at increased risk of thrombosis with an enhanced risk of bleeding. We aimed to explore the role of anti-factor Xa levels in optimizing the high-intensity anticoagulation’s safety and efficacy and finding possible associations between D-dimer levels, cytokine storm markers, and COVID-19-induced coagulopathy or thrombophilia. Methods: Retrospective cohort study conducted on 69 critically ill COVID-19 patients who received three regimens of higher intensity anticoagulation. Results: Seventeen patients (24.6%) received high-dose enoxaparin prophylaxis, 29 patients (42%) received therapeutic doses of enoxaparin, and 23 patients (33.3%) were on therapeutic unfractionated heparin infusion. Fewer than one-third of the whole cohort ( n = 22; 31.8%) achieved the target range of anti-factor Xa. The patients were divided into three subgroups based on anti-factor Xa target status within each anticoagulation regimen; when compared, the only association observed among them was for interleukin-6 levels, which were significantly higher in both the “above the expected range” and “below the expected range” groups compared with the “within the expected range” group ( p = 0.009). Major bleeding episodes occurred in 14 (20.3%) patients and were non-significantly more frequent in the “below the expected anti-factor Xa range group” ( p = 0.415). Seven patients (10.1%) developed thrombosis. The majority of patients had anti-factor Xa levels below the expected ranges (four patients, 57.1%). Conclusion: Conventional anti-factor Xa ranges may not be appropriate as a predictive surrogate for bleeding in critically ill COVID-19. The clinical decision to initiate therapeutic anticoagulation preemptively may be individualized according to thrombosis and bleeding risks. Cytokine storm markers, namely, interleukin-6, may play a role in COVID-19-induced coagulopathy or thrombophilia.

scholarly journals Anti-inflammatory Therapy for Coronary Atherosclerotic Heart Disease: Unanswered Questions Behind Existing Successes

2021 ◽  
Vol 7 ◽  
Author(s):  
Jun Ma ◽  
Xiaoping Chen
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Heart Disease ◽  
Human Health ◽  
Interleukin 6 ◽  
Interleukin 1Β ◽  
Outcome Study ◽  
Receptor Antagonists ◽  
Interleukin 6 Receptor ◽  
Anti Inflammatory

Coronary atherosclerotic heart disease is a serious threat to human health. The results of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study published in 2017 put an end to the perennial debate about the anti-inflammatory treatment of coronary atherosclerotic heart disease. In addition to interleukin 1β monoclonal antibody, interleukin 6 receptor antagonists and colchicine have also shown exciting results in clinical trials within the last 3 years. However, behind these successes, questions remain that need to be addressed. In this review, we summarize the successes and existing doubts of interleukin 1β antibodies, interleukin 6 receptor antagonists, and colchicine in the anti-inflammatory treatment of coronary atherosclerotic heart disease.

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