In a recent systematic review and meta-analysis published in PLOS ONE, researchers evaluated the use of colchicine in coronavirus disease 2019 (COVID-19) patients.
COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has been classified into many phases, such as initiation, pulmonary, and hyper-inflammation, with specified treatments for each phase. While immune-modulating and antiviral drugs are recommended for the initiation and pulmonary stages, anti-inflammatory drugs lower the hyper-inflammation driven by the pro-inflammatory cytokines, chemokines, and C-reactive protein (CRP) in patients with severe COVID-19.
Being anti-inflammatory, colchicine has been implicated as a potential treatment for the cytokine storm during SARS-CoV-2 infection, with various trials underway. Among the different randomized controlled trials (RCTs) conducted, the RECOVERY and COLCORONA trials are the most extensive. Although meta-analyses in this context have been previously carried out, they were of lower statistical power due to small-to-moderate size and biased observational studies.
About the study
In the present study, researchers systematically reviewed and meta-analyzed all available RCTs performed on the use of colchicine for COVID-19 treatment. The PubMed and Cochrane databases were searched for extracting RCTs available until June 14, 2021. Additionally, the authors identified preprints and grey literature from clinicaltrials.gov, medRxiv, and Google Scholar resources.
Studies were eligible if they had confirmed COVID-19 cases with a positive test [polymerase chain reaction (PCR)] treated with colchicine and a control/placebo group receiving standard therapy. The outcomes of interest were severity of COVID-19, mechanical ventilation, all-cause mortality, and pre-and post-treatment changes in laboratory parameters. Reviews, case reports, and observational studies were eliminated after screening. Studies with children aged 18 years or below, non-human subjects, or pregnant females were excluded from the meta-analysis.
Two investigators extracted data on – the publication year, author(s), study design, gender, sample size, participants’ age, the number of subjects in treatment and control/placebo groups, dosage, D-dimer (biomarker for inflammation), and CRP levels among others. The extracted studies’ quality was independently examined using RoB2, a revised risk of a bias assessment tool for RCTs.
Relative risks (RRs) and odds ratios (ORs) were extracted with 95% confidence intervals (CIs) for dichotomous outcomes. Median values of D-dimer and CRP levels were extracted for continuous outcomes. Wan’s method converted these values to mean and standard error. I2 statistic was used to measure the homogeneity among studies, with an I2 of 25% considered low, 25% to 50% moderate, and high if > 50%.
The search criteria yielded 1152 records initially; duplicate removal and extensive screening resulted in five RCTs – COLCORONA, GRECCO, RECOVERY, COLORIT, and Lopes et al. for the qualitative analysis. Overall, the meta-analysis was performed on 16,048 SARS-CoV-2-positive patients, with 7957 patients randomized for colchicine treatment and the remaining for standard care (controls). Of these, three studies investigated the severity of COVID-19 in patients, and colchicine was found to decrease COVID-19 severity significantly. All five selected studies reported/included all-cause mortality in their investigations, and no significant differences were observed in all-cause mortality among patients across the treatment and control groups. Four studies were included in the quantitative analysis, and the authors observed no statistically significant decrease in mechanical ventilation among the colchicine and control groups with moderately high heterogeneity, i.e., I2 = 74%.
In a leave-one-out sensitivity analysis where RCTs were excluded from the analysis individually, the in-study heterogeneity was not reduced. However, the colchicine recipients had lower odds of mechanical ventilation than standard care patients (controls) when the RCT and RECOVERY were excluded. D-dimer levels were not statistically different among colchicine-treated subjects or standard care patients. The researchers observed that colchicine reduced CRP levels significantly post-treatment, while control patients displayed no such reduction. RoB2 evaluation found a low risk of bias in the included studies.
The study findings showed that colchicine treatment significantly reduced CRP levels and COVID-19 severity without significant differences in D-dimer levels, all-cause mortality, and mechanical ventilation. Nonetheless, the COLORIT and GRECCO trials reported a marginal increase in D-dimer levels associated with colchicine treatment.
A few limitations of the meta-analysis include evaluating a small number of RCTs besides the non-uniform duration of colchicine treatment across the RCTs, which might contribute to varied results. The study findings indicate that colchicine therapy might be potentially helpful for COVID-19 patients for reducing disease severity and that clinicians might consider its use in combination or alone. However, more trials are required in the future to assess its safety and efficacy profiles effectively.