Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis, first update.

OBJECTIVES: Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to update the data in a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients. METHODS: Data sources were Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google from 8th October 2020 till 24th February 2021. Eligible studies were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. The participants were hospitalized COVID-19 patients, and intervention was tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs with a random effects model and evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach. RESULTS: Of 1600 citations, eight RCTs and 28 cohorts were eligible. The eight RCTs had low risk of bias, and with 6311 patients they examined the effect of tocilizumab on short-term mortality; pooled RR was 0.91 (95%CI 0.78-1.07, I2 25%). Only the REMAP-CAP and RECOVERY trials, with the majority of their patients on concomitant corticosteroids, showed lower 30-day mortality with tocilizumab use: RR 0.74 (95%CI 0.59-0.93) and 0.89 (95%CI 0.81-0.97), respectively. Seven RCTs, with 5391 patients, examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.84 (95%CI 0.76-0.93), I2 0%, with a corresponding number needed to treat of 20 (95%CI 14.3-33.3). Eight RCTs, with 5340 patients, examined the effect of tocilizumab on a composite of poor outcome; pooled RR was 0.82 (95%CI 0.76-0.90, I2 3%). Data from the RCTs showed a lower risk of infections and no higher risk of serious adverse events with tocilizumab: pooled RR 0.67 (95%CI 0.45-0.99, eight RCTs) and 0.85 (95%CI 0.63-1.16, seven RCTs), respectively. Among 28 cohorts with 15 484 patients, the pooled adjusted RR for mortality was 0.53 (95%CI 0.43-0.67, I2 76%). CONCLUSIONS: Cumulative high-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized patients with severe COVID-19. Moderate-certainty evidence shows that tocilizumab reduces the risk of poor outcome and the risk of secondary infections in hospitalized COVID-19 patients. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment.

Mortality, viral clearance, and other clinical outcomes of hydroxychloroquine in COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

Many meta-analyses have been published about the efficacy of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19). Most of them included observational studies, and few have assessed HCQ as a prophylaxis or evaluated its safety profile. We searched multiple databases and preprint servers for randomized controlled trials (RCTs) that assessed HCQ for the treatment or prevention of COVID-19. We summarized the effect of HCQ on mortality, viral clearance, and other clinical outcomes. Out of 768 papers screened, 21 RCTs with a total of 14,138 patients were included. A total of 9 inpatient and 3 outpatient RCTs assessed mortality in 8596 patients with a pooled risk difference of 0.01 (95% confidence interval [CI] 0.00-0.03, I2  = 1%, p = 0.07). Six studies assessed viral clearance at 7 days with a pooled risk ratio (RR) of 1.11 (95% CI 0.86-1.42, I2  = 61%, p = 0.44) and 5 studies at 14 days with a pooled RR of 0.96 (95% CI 0.89-1.04, I2  = 0%, p = 0.34). Several trials showed no significant effect of HCQ on other clinical outcomes and. Five prevention RCTs with 5012 patients found no effect of HCQ on the risk of acquiring COVID-19. Thirteen trials showed that HCQ was associated with increased risk of adverse events. We observed, with high level of certainty of evidence, that HCQ is not effective in reducing mortality in patients with COVID-19. Lower certainty evidence also suggests that HCQ neither improves viral clearance and other clinical outcomes, nor prevents COVID-19 infection in patients with high-risk exposure. HCQ is associated with an increased rate of adverse events.

Cardiac Toxicity of Chloroquine or Hydroxychloroquine in Patients With COVID-19: A Systematic Review and Meta-regression Analysis.

OBJECTIVE: To systematically review the literature and to estimate the risk of chloroquine (CQ) and hydroxychloroquine (HCQ) cardiac toxicity in patients with coronavirus disease 2019 (COVID-19). METHODS: We searched multiple data sources including PubMed/MEDLINE, Ovid Embase, Ovid EBM Reviews, Scopus, and Web of Science and medrxiv.org from November 2019 through May 27, 2020. We included studies that enrolled patients with COVID-19 treated with CQ or HCQ, with or without azithromycin, and reported on cardiac toxic effects. We performed a meta-analysis using the arcsine transformation of the different incidences. RESULTS: A total of 19 studies with a total of 5652 patients were included. The pooled incidence of torsades de pointes arrhythmia, ventricular tachycardia, or cardiac arrest was 3 per 1000 (95% CI, 0-21; I 2 =96%) in 18 studies with 3725 patients. Among 13 studies of 4334 patients, the pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias was 5% (95% CI, 1-11; I 2 =98%). The pooled incidence of change in QTc from baseline of 60 milliseconds or more or QTc of 500 milliseconds or more was 9% (95% CI, 3-17; I 2 =97%). Mean or median age, coronary artery disease, hypertension, diabetes, concomitant QT-prolonging medications, intensive care unit admission, and severity of illness in the study populations explained between-studies heterogeneity. CONCLUSION: Treatment of patients with COVID-19 with CQ or HCQ is associated with an important risk of drug-induced QT prolongation and relatively higher incidence of torsades de pointes, ventricular tachycardia, or cardiac arrest. Therefore, these agents should not be used routinely in the management of COVID-19 disease. Patients with COVID-19 who are treated with antimalarials for other indications should be adequately monitored.

Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis.

OBJECTIVES: Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to perform a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients. METHODS: Data sources were Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google up to October 8, 2020. Study eligibility criteria were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs and adjusted RRs from cohorts, separately. We evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach. RESULTS: Of 1156 citations, 24 studies were eligible (five RCTs and 19 cohorts). Five RCTs at low risk of bias, with 1325 patients, examined the effect of tocilizumab on short-term mortality; pooled RR was 1.09 (95%CI 0.80-1.49, I2 = 0%). Four RCTs with 771 patients examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.71 (95%CI 0.52-0.96, I2 = 0%), with a corresponding number needed to treat of 17 (95%CI 9-100). Among 18 cohorts at moderate risk of bias with 9850 patients, the pooled adjusted RR for mortality was 0.58 (95%CI 0.51-0.66, I2 = 2.5%). This association was observed over all degrees of COVID-19 severity. Data from the RCTs did not show a higher risk of infections or adverse events with tocilizumab: pooled RR 0.63 (95%CI 0.38-1.06, five RCTs) and 0.83 (95%CI 0.55-1.24, five RCTs), respectively. CONCLUSIONS: Cumulative moderate-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized COVID-19 patients. While RCTs showed that tocilizumab did not reduce short-term mortality, low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality. We did not observe a higher risk of infections or adverse events with tocilizumab use. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment.

Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis.

OBJECTIVES: Clinical studies of chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 disease reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin on outcomes of COVID-19 patients. METHODS: We searched multiple databases, preprints and grey literature up to 17 July 2020. We pooled only adjusted-effect estimates of mortality using a random-effect model. We summarized the effect of CQ or HCQ on viral clearance, ICU admission/mechanical ventilation and hospitalization. RESULTS: Seven randomized clinical trials (RCTs) and 14 cohort studies were included (20 979 patients). Thirteen studies (1 RCT and 12 cohort studies) with 15 938 hospitalized patients examined the effect of HCQ on short-term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96-1.15, I2 = 0%). Six cohort studies examined the effect of the HCQ+azithromycin combination with a pooled adjusted OR of 1.32 (95% CI 1.00-1.75, I2 = 68.1%). Two cohort studies and four RCTs found no effect of HCQ on viral clearance. One small RCT demonstrated improved viral clearance with CQ and HCQ. Three cohort studies found that HCQ had no significant effect on mechanical ventilation/ICU admission. Two RCTs found no effect for HCQ on hospitalization risk in outpatients with COVID-19. CONCLUSIONS: Moderate certainty evidence suggests that HCQ, with or without azithromycin, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19 or risk of hospitalization in outpatients with COVID-19.

Trends in the Explanatory or Pragmatic Nature of Cardiovascular Clinical Trials Over 2 Decades.

Importance: Pragmatic trials test interventions using designs that produce results that may be more applicable to the population in which the intervention will be eventually applied. Objective: To investigate how pragmatic or explanatory cardiovascular (CV) randomized clinical trials (RCT) are, and if this has changed over time. Data Source: Six major medical and CV journals, including New England Journal of Medicine, Lancet, JAMA, Circulation, European Heart Journal, and Journal of the American College of Cardiology. Study Selection: All CV-related RCTs published during 2000, 2005, 2010, and 2015 were identified and included. Data Extraction and Synthesis: Included RCTs were assessed by 2 independent adjudicators with expertise in RCT and CV medicine. Main Outcomes and Measures: The outcome measure was the level of pragmatism evaluated using the Pragmatic Explanatory Continuum Index Summary (PRECIS)-2 tool, which uses a 5-point ordinal scale (ranging from very pragmatic to very explanatory) across 9 domains of trial design, including eligibility, recruitment, setting, organization, intervention delivery, intervention adherence, follow-up, primary outcome, and analysis. Results: Of 616 RCTs, the mean (SD) PRECIS-2 score was 3.26 (0.70). The level of pragmatism increased over time from a mean (SD) score of 3.07 (0.74) in 2000 to 3.46 (0.67) in 2015 (P < .001 for trend; Cohen d relative effect size, 0.56). The increase occurred mainly in the domains of eligibility, setting, intervention delivery, and primary end point. PRECIS-2 score was higher for neutral trials than those with positive results (P < .001) and in phase III/IV trials compared with phase I/II trials (P < .001) but similar between different sources of funding (public, industry, or both; P = .38). More pragmatic trials had more sites, larger sample sizes, longer follow-ups, and mortality as the primary end point. Conclusions and Relevance: The level of pragmatism increased moderately over 2 decades of CV trials. Understanding the domains of current and future clinical trials will aid in the design and delivery of CV trials with broader application.