RESUMO
Background: Anticoagulants are promising regimens for treating coronavirus disease 2019 (COVID-19). However, whether prophylactic or intermediate-to-therapeutic dosage is optimal remains under active discussion. Methods: We comprehensively searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, ClinicalTrials, and MedRxiv databases on April 26, 2022. Two independent researchers conducted literature selection and data extraction separately according to predetermined criteria. Notably, this is the first meta-analysis on COVID-19, taking serious consideration regarding the dosage overlap between the 2 comparison groups of prophylactic anticoagulation (PA) and intermediate-to-therapeutic anticoagulation (I-TA). Results: We included 11 randomized controlled trials (RCTs) and 36 cohort studies with 27,051 COVID-19 patients. By analyzing all the RCTs, there was no significant difference in mortality between the PA and I-TA groups, which was further confirmed by trial sequential analysis (TSA) (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.71-1.22; P = 0.61; TSA adjusted CI: 0.71-1.26). The rate of major bleeding was remarkably higher in the I-TA group than in the PA group, despite adjusting for TSA (OR: 1.73; 95% CI: 1.15-2.60; P = 0.009; TSA adjusted CI: 1.09-2.58). RCTs have supported the beneficial effect of I-TA in reducing thrombotic events. After including all studies, mortality in the I-TA group was significantly higher than in the PA group (OR: 1.38; 95% CI: 1.15-1.66; P = 0.0005). The rate of major bleeding was similar to the analysis from RCTs (OR: 2.24; 95% CI: 1.86-2.69; P < 0.00001). There was no distinct difference in the rate of thrombotic events between the 2 regimen groups. In addition, in both critical and noncritical subgroups, I-TA failed to reduce mortality but increased major bleeding rate compared with PA, as shown in meta-analysis of all studies, as well as RCTs only. Meta-regression of all studies suggested that there was no relationship between the treatment effect and the overall risk of mortality or major bleeding (P = 0.14, P = 0.09, respectively). Conclusion: I-TA is not superior to PA for treating COVID-19 because it fails to lower the mortality rate but increases the major bleeding rate in both critical and noncritical patients.
RESUMO
Background: Interleukin-6 (IL-6) is known to be detrimental in coronavirus disease 2019 (COVID-19) because of its involvement in driving cytokine storm. This systematic review and meta-analysis aimed to assess the safety and efficacy of anti-IL-6 signaling (anti-IL6/IL-6R/JAK) agents on COVID-19 based on the current evidence. Methods: Studies were identified through systematic searches of PubMed, EMBASE, ISI Web of Science, Cochrane library, ongoing clinical trial registries (clinicaltrials.gov), and preprint servers (medRxiv, ChinaXiv) on August 10, 2020, as well as eligibility checks according to predefined selection criteria. Statistical analysis was performed using Review Manager (version 5.3) and STATA 12.0. Results: Thirty-one studies were included in the pooled analysis of mortality, and 12 studies were identified for the analysis of risk of secondary infections. For mortality analysis, 5630 COVID-19 cases including 2,132 treated patients and 3,498 controls were analyzed. Anti-IL-6 signaling agents plus standard of care (SOC) significantly decreased the mortality rate compared to SOC alone (pooled OR = 0.61, 95% CI 0.45-0.84, p = 0.002). For the analysis of secondary infection risk, 1,624 patients with COVID-19 including 639 treated patients and 985 controls were included, showing that anti-IL-6 signaling agents did not increase the rate of secondary infections (pooled OR = 1.21, 95% CI 0.70-2.08, p = 0.50). By contrast, for patients with critical COVID-19 disease, anti-IL-6 signaling agents failed to reduce mortality compared to SOC alone (pooled OR = 0.75, 95% CI 0.42-1.33, p = 0.33), but they tended to increase the risk of secondary infections (pooled OR = 1.85, 95% CI 0.95-3.61, p = 0.07). A blockade of IL-6 signaling failed to reduce the mechanical ventilation rate, ICU admission rate, or elevate the clinical improvement rate. Conclusion: IL-6 signaling inhibitors reduced the mortality rate without increasing secondary infections in patients with COVID-19 based on current studies. For patients with critical disease, IL-6 signaling inhibitors did not exhibit any benefit.