'Misleading' Results in Colchicine COVID-19 Trials Meta-Analysis

Jeff Craven

November 23, 2021

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A new meta-analysis appears to show that colchicine has no benefit as a treatment for COVID-19, but its inclusion of trials studying differing patient populations and testing different outcomes led to "misleading" results, says a researcher involved in one of the trials.

The meta-analysis, which includes data from the recent Randomised Evaluation of COVID-19 therapy (RECOVERY) trial, was published in RMD Open on November 22.

Kedar Gautambhai Mehta, MBBS, MD, of the GMERS Medical College Gotri in Vadodara, Gujarat, India, and colleagues included outcomes from six studies of 16,148 patients with COVID-19 who received colchicine or supportive care. They evaluated the efficacy outcomes of mortality, need for ventilation, intensive care unit (ICU) admission, and length of stay in hospital, as well as safety outcomes of adverse events, serious adverse events, and diarrhea.

The studies in the meta-analysis included a randomized, controlled trial (RCT) of 105 patients hospitalized with COVID-19 in Greece, the international, open-label RECOVERY RCT of 11,340 patients hospitalized with COVID-19, an RCT of 72 hospitalized patients with moderate or severe COVID-19 in Brazil, an RCT of 100 patients hospitalized with COVID-19 in Iran, the international COLCORONA trial of 4488 patients with COVID-19 who were treated with colchicine or placebo on an outpatient basis, and the randomized COLORIT trial of 43 patients hospitalized with COVID-19 in Russia.

Studies "Asked Very Different Questions" About Colchicine

Commenting on the meta-analysis, Michael H. Pillinger, MD, a rheumatologist and professor of medicine, biochemistry, and molecular pharmacology with NYU Grossman School of Medicine in New York, said the authors combined studies "that are not comparable and that asked very different questions." Two of the studies in the meta-analysis are very large, and four are very small, which skews the results, he explained.

Dr Michael Pillinger

"The larger studies therefore drive the outcome, and while the small studies are potentially insight-providing, the large studies are the only ones worth giving our attention to in the context of the meta-analysis," he said. The two largest studies ― RECOVERY and COLCORONA ― taken together show no benefit for colchicine as a treatment, even though the former demonstrated no benefit and the latter did show a benefit, explained Pillinger, a co–principal investigator for the COLCORONA trial in the United States.

The studies were designed differently and should not have been included in the same analysis, Pillinger argued. In the case of COLCORONA, early treatment with colchicine was the intervention, whereas RECOVERY focused on hospitalized patients.

"In designing [COLCORONA], the author group (of whom I was a member) expressly rejected the idea that colchicine might be useful for the sicker hospitalized patients, based on the long experience with colchicine of some of us as rheumatologists," Pillinger said.

"In short, COLCORONA proved a benefit of colchicine in outpatient COVID-19 and its authors presumed there would be no inpatient benefit; RECOVERY went ahead and proved a lack of inpatient benefit, at least when high-dose steroids were also given," he said. "While there is no conflict between these results, the combination of the two studies in this meta-analysis suggests there might be no benefit for colchicine overall, which is misleading and can lead physicians to reject the potential of outpatient colchicine, even for future studies."

Pillinger said he still believes colchicine has potential value as a COVID-19 treatment option for patients with mild disease, "especially for low-vaccine rate, resource-starved countries.

"It would be unfortunate if meta-analyses such as this one would put a stop to colchicine's use, or at least its further investigation," he said.

Study Details

The authors of the study assessed heterogeneity of the trials' data across the outcomes using an I2 test. They evaluated the quality of the evidence for the outcomes using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE).

The results of their meta-analysis showed that colchicine offered no significant improvement in mortality in six studies (risk difference, -0.0; 95% CI, -0.01 to 0.01; I2 = 15%). It showed no benefit with respect to requiring ventilatory support in five studies of 15,519 patients (risk ratio, 0.67; 95% CI, 0.38 – 1.21; I2 = 47%); being admitted to the ICU in three studies with 220 patients (RR, 0.49; 95% CI, 0.19 to 1.25; I2 = 34%); and length of stay while in the hospital in four studies of 11,560 patients (mean difference, -1.17; 95% CI, -3.02 to 0.67; I2 = 77%).

There was no difference in serious adverse events in three studies with 4665 patients (RD, -0.01; 95% CI, -0.02 to 0.00; I2 = 28%) for patients who received colchicine compared with supportive care alone. Patients who received colchicine were more likely to have a higher rate of adverse events (RR, 1.58; 95% CI, 1.07 – 2.33; I2 = 81%) and to experience diarrhea (RR, 1.93; 95% CI, 1.62 – 2.29; I2 = 0%) than were patients who received supportive care alone. The researchers note that for most outcomes, the GRADE quality of evidence was moderate.

"Our findings on colchicine should be interpreted cautiously due to the inclusion of open-labeled, randomized clinical trials," Mehta and colleagues write. "The analysis of efficacy and safety outcomes are based on a small number of RCTs in control interventions."

The authors reported no relevant financial relationships. Pillinger is co–principal investigator of the US component of the COLCORONA trial; he reported no other relevant conflicts of interest.

RMD Open. Published online November 23, 2021. Full text

Jeff Craven is an independent journalist living in Wilmington, Delaware.

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