Convalescent Plasma for Patients Hospitalized With Coronavirus Disease 2019: A Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials

Abstract

Current evidence from randomized controlled trials (RCTs) and systematic reviews on the utility of convalescent plasma (CP) in patients with coronavirus disease 2019 (COVID-19) suggests a lack of benefit. We conducted an updated meta-analysis of RCTs with trial sequential analysis to investigate whether convalescent plasma is futile in reducing mortality in patients hospitalized with COVID-19. We searched 6 databases from December 1, 2019 to August 1, 2021 for RCTs comparing the use of CP with standard of care or transfusion of non-CP standard plasma in patients with COVID-19. The risk of bias was assessed using the Cochrane Risk-of-Bias 2 Tool. Random effects (DerSimonian and Laird) meta-analyses were conducted. The primary outcome was the aggregate risk for in-hospital mortality between both arms. We conducted a trial sequential analysis (TSA) based on the pooled relative risks (RRs) for in-hospital mortality. Secondary outcomes included the pooled RR for receipt of mechanical ventilation and mean difference in hospital length of stay. We included 18 RCTs (8702 CP, 7906 control). CP was not associated with a significant mortality benefit (RR: 0.95, 95%-CI: 0.86-1.04, P = .27, high certainty). Subgroup analysis did not find any significant differences (p_interaction = 0.30) between patients who received CP within 8 days of symptom onset (RR: 0.97, 95%-CI: 0.79-1.19, P = .80), or after 8 days (RR: 0.79, 95%-CI: 0.57-1.10, P = .16). TSA based on a RR reduction of 10% from a baseline mortality of 20% found that CP was not effective, with the pooled effect within the boundary for futility. CP did not significantly reduce the requirement for mechanical ventilation (RR: 1.00, 95%-CI: 0.91-1.10, P = .99, moderate certainty) or hospital length of stay (+1.32, 95%-CI: -1.86 to +4.52, P = .42, low certainty). CP does not improve relevant clinical outcomes in patients with COVID-19, especially in severe disease. The pooled effect of mortality was within the boundary of futility, suggesting the lack of benefit of CP in patients hospitalized with COVID-19.

Keywords: Convalescent plasma; Coronavirus disease 2019; Meta-analysis; Mortality; Severe acute respiratory syndrome coronavirus 2.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-analyses Flow Diagram.

Fig. 2

Pooled in-hospital mortality for patients receiving convalescent plasma and standard of care for COVID-19.

Fig. 3

Funnel plot after correcting for small-study effects using the trim-and-fill (R₀) estimator.

Fig. 4

Trial sequential analysis for a baseline mortality rate of 20%. As the RECOVERY trial had found no significant benefit at a relative risk reduction (RRR) in mortality of 20%, modelled our TSA based on a 10% RRR in mortality to further elicit the effect of convalescent plasma. The required information size is 17,257, and this is not achieved. The cumulative Z-curve (red line) does not cross the boundary for conventional (light-blue dotted lines) or TSA-adjusted (upper and lower-most curves) boundaries for benefit or harm. The Z-curve is within the boundary of futility (triangular lines beginning from the middle of the graph).