The efficacy and safety of convalescent plasma for COVID-19 patients: a meta-analysis based on double-blinded parallel-arm randomized placebo-controlled trials.

backgroundConvalescent plasma (CP) showed promising benefits in previous coronavirus pandemics regarding efficacy and safety. However, the efficacy of CP from COVID-19 patients remains controversial and uncertain based on current randomized controlled trials (RCTs). There is an urgent need to establish the efficacy and safety of CP for COVID-19 patients as soon as possible.

objectiveTo verify the efficacy and safety of CP using high-quality, double-blinded, parallel-arm, placebo-controlled randomized clinical trials, and to provide evidence-based support for the clinical application of CP against COVID-19.

methodsElectronic databases such as Embase, PubMed, and Web of Science were searched from inception to October 18, 2024. This meta-analysis synthesized dichotomous outcomes, including 28-day mortality, hospitalization rates, invasive mechanical ventilation, adverse events (AEs), and serious AEs, using an intention-to-treat (ITT) analysis. Statistical analysis was performed using Review Manager (RevMan) 5.4.1, the Mantel-Haenszel (M-H) statistical method, and a random effects (RE) analysis model. Risk ratios (RRs) and their 95% confidence intervals (CIs) were used as effect measures. Two reviewers independently searched, screened, and included eligible clinical trials, extracted relevant data, and assessed risks of bias (ROB) using the Cochrane ROB tool 1.0 and RevMan 5.4.1. The RRs and 95% CIs in this meta-analysis were computed as dichotomous outcomes. Statistical heterogeneity, subgroup analysis, and sensitivity analysis were conducted to explore heterogeneities and their causes. The quality of evidence was evaluated, and recommendations for clinical practice were based on the GRADE approach. The prospective meta-analysis protocol was registered on PROSPERO.

resultsA total of 996 references were identified through database and manual searches. Nine eligible double-blinded, parallel-arm, placebo-controlled randomized clinical trials, involving 1898 subjects in the intervention group and 1696 in the control group, were included in the meta-analysis. Seven, four, three, three, and three trials were judged as low ROB for mortality, hospitalization rates, invasive mechanical ventilation, AEs, and serious AEs, respectively. The remaining trials were deemed high-risk for their respective outcomes. The meta-analysis on hospitalization rates was abandoned due to high heterogeneity (I²=92%) among the included trials. The RRs, 95% CIs, and P-values were as follows: 0.78 [0.62, 0.97], P = 0.03 for mortality; 0.84 [0.50, 1.42], P = 0.51 for invasive mechanical ventilation; 1.01 [0.78, 1.32], P = 0.92 for AEs; and 0.96 [0.73, 1.28], P = 0.80 for serious AEs, all with low or medium levels of heterogeneity. These results suggest that CP infusion in COVID-19 patients reduced mortality by 22% and exhibited excellent safety without reducing the incidence of invasive mechanical ventilation. Sensitivity analysis on mortality, using the combined effect measure (RR 0.83 [0.66, 1.06], I²=0%, Z = 1.46, P = 0.14) after excluding the study by O'Donnell, showed no significant difference between the intervention and control groups, implying that the excluded study might have a stronger effect in reducing mortality. Subgroup analysis based on age indicated that CP therapy in COVID-19 patients aged ≤ 60 years reduced mortality by 36%. Sensitivity and subgroup analyses for other outcomes demonstrated robust pooled results. The PROSPERO registration code is CRD42022324324.

conclusionsAdministration of CP to COVID-19 patients, especially those aged ≤ 60 years, may reduce mortality with excellent safety without more AEs, and serious AEs, but does not reduce the incidence of invasive mechanical ventilation.