Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Abstract

Background: Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed.

Methods and findings: This is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62-0.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40-1.37; p = 0.34, I2 = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80-1.11; p = 0.48, I2 = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63-0.94; p = 0.009, I2 = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial. Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97-1.19; p = 0.17; I2 = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96-1.18; p = 0.21; I2 = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01-2.87; p < 0.00001; I2 = 90%; 6 trials; very low certainty). Meta-analysis showed no evidence of a difference between lopinavir-ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39-1.04; p = 0.07, I2 = 0%; 2 trials; very low certainty) or nonserious adverse events (RR 1.14; 95% CI 0.85-1.53; p = 0.38, I2 = 75%; 2 trials; very low certainty). Meta-analysis showed no evidence of a difference between convalescent plasma versus standard care on all-cause mortality (RR 0.60; 95% CI 0.33-1.10; p = 0.10, I2 = 0%; 2 trials; very low certainty). Five single trials showed statistically significant results but were underpowered to confirm or reject realistic intervention effects. None of the remaining trials showed evidence of a difference on our predefined outcomes. Because of the lack of relevant data, it was not possible to perform other meta-analyses, network meta-analysis, or individual patient data meta-analyses. The main limitation of this living review is the paucity of data currently available. Furthermore, the included trials were all at risks of systematic errors and random errors.

Conclusions: Our results show that dexamethasone and remdesivir might be beneficial for COVID-19 patients, but the certainty of the evidence was low to very low, so more trials are needed. We can exclude the possibility of hydroxychloroquine versus standard care reducing the risk of death and serious adverse events by 20% or more. Otherwise, no evidence-based treatment for COVID-19 currently exists. This review will continuously inform best practice in treatment and clinical research of COVID-19.

Fig 1. PRISMA flow diagram.

BIOSIS, Biosciences Information Services; CENTRAL, Cochrane Central Register of Controlled Trials; CINAHL, Current Index to Nursing and Allied Health Literature; EMBASE, Excerpta Medica database; LILCAS, Latin American and Caribbean Health Sciences Literature; MEDLINE, Medical Literature Analysis and Retrieval System Online; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis; SCIsearch, Science Citation Index Search.

Fig 2. Meta-analysis of remdesivir versus placebo on all-cause mortality.

ACTT-1-2020, Adaptive COVID-19 Treatment Trial 1; CI, confidence interval.

Fig 3. Trial sequential analysis of remdesivir versus placebo on all-cause mortality.

Trial sequential analysis on remdesivir versus placebo on all-cause mortality in 2 trials at high risk of bias. The DARIS was calculated based on a mortality proportion in the control group of 10.7%; risk ratio reduction of 20% in the experimental group; type I error of 3.3%; and type II error of 10% (90% power). Diversity was 62%. The required information size was 23,310 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm. The cumulative Z‐curve did not cross the inner‐wedge futility line (red outward sloping lines nor the DARIS). The green dotted line shows conventional boundaries (alpha 5%). DARIS, diversity‐adjusted required information size; Pc, proportion of participants in control group; RRR, relative risk reduction.

Fig 4. Meta-analysis of remdesivir versus placebo on serious adverse events.

ACTT-1-2020, Adaptive COVID-19 Treatment Trial 1; CI, confidence interval.

Fig 5. Trial sequential analysis of remdesivir versus placebo on serious adverse events.

Trial sequential analysis on remdesivir versus placebo on serious adverse events in 2 trials at high risk of bias. The DARIS was calculated based on a proportion in the control group of 26.8%; risk ratio reduction of 20% in the experimental group; type I error of 3.3%; and type II error of 10% (90% power). Diversity was 0%. The required information size was 2,970 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines). The cumulative Z‐curve did not cross the inner‐wedge futility line (red outward sloping lines nor the DARIS). The green dotted line shows conventional boundaries (alpha 5%). DARIS, diversity‐adjusted required information size; Pc, proportion of participants in control group; RRR, relative risk reduction.