Colchicine Shows Promise in COVID-19 Patients, With Caveats

Hospitalized patients with COVID-19 who received colchicine, an anti-inflammatory drug traditionally used to treat gout and rheumatic disease, had improved time to clinical deterioration versus standard of care, a randomized open-label trial from Greece found.

Clinical deterioration, defined as a decline of 2 points on a 7-grade clinical status scale, occurred in one patient in the colchicine group versus seven in the control group (OR 0.11, 95% CI 0.01-0.96, P=0.046), reported Spyridon G. Deftereos, MD, PhD, of the University of Athens, and colleagues in JAMA Network Open.

However, there were no significant differences between groups when examining troponin values and C-reactive protein levels, the authors wrote.

One major limitation to the study is that due to "the relatively small number of clinical events, the statistical robustness of the results is limited," despite the "striking" arithmetic difference between the two groups. Indeed, Deftereos and colleagues said enrollment in the trial was "slow" and was terminated less than a month later due to the "rapid flattening of the curve" in Greece.

Given its anti-inflammatory properties, colchicine has also been studied in cardiovascular prevention, albeit with mixed results.

In reviewing the literature, Deftereos's group found that colchicine has "a favorable safety-benefit profile among patients with cardiovascular disease." This, plus its anti-inflammatory effects "suggest that colchicine might combine anti-inflammatory action with an acceptable safety profile, leading to the hypothesis that it might be a safe and effective anti-inflammatory treatment choice for COVID-19," they wrote.

In the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention (GRECCO), researchers examined hospitalized patients with COVID-19 from April 3 to April 27, when enrollment stopped.

Primary endpoints included not only time to deterioration (defined as 2 points on a 7-grade clinical status scale, ranging from resuming normal activities to death), but also maximum high-sensitivity cardiac troponin level and time for C-reactive protein to reach more than 3 times the upper reference limit.

They randomized 105 patients with laboratory-confirmed SARS-CoV-2 infection and at least two clinical symptoms from 16 hospitals in Greece to receive either colchicine or standard medical treatment for up to 3 weeks. Approximately 60% were men, with a median age of 64, and 60%-65% had a clinical status score of 4. Nearly all patients had received hydroxychloroquine or chloroquine and azithromycin.

Seven patients in the control group met the primary endpoint of clinical deterioration, of whom five were intubated and ventilated mechanically; three died shortly afterward. The one patient meeting this endpoint in the colchicine group needed invasive mechanical ventilation and died subsequently in the ICU. Cumulative event-free 10 day survival was 97% in the colchicine group versus 83% among controls.

Adverse events were similar between groups, though diarrhea was more frequent in the colchicine group than in controls (25 vs nine patients, respectively).

No difference was seen in maximal high-sensitivity cardiac troponin levels; Deftereos and colleagues described increases as "low to modest, far below what cardiologists are used to encountering in patients with acute coronary syndromes or myocarditis."

C-reactive protein levels also did not differ significantly. The researchers said concurrent administration of other drugs with anti-inflammatory action, such as chloroquine or azithromycin, might be part of the reason.

An accompanying editorial by Amir B. Rabbani, MD, and two colleagues at the University of California Los Angeles said the lack of reduction in troponin levels could partly be explained by the trial's inclusion criteria, which did not require an elevated troponin level, as well as that median troponin levels in the trial "were quite low."

But they highlighted an unexpected finding: the significant reduction in dimerized plasma D fragment levels in the group receiving colchicine.

"This is an important and novel finding given that it suggests colchicine's mechanism of action to treat COVID-19 may be antithrombotic as well as anti-inflammatory," the editorialists wrote.

Other limitations to the data from Deftereos and colleagues include that it was an open-label study, and that other laboratory parameters that may have explained the effect of colchicine on inflammatory pathways could not be evaluated due to logistical constraints.

Still, Rabbani and colleagues praised the study for "several intriguing hypotheses" about how colchicine may be effective in COVID-19, and recommended future studies to address whether there is a cardioprotective effect of the drug for patients presenting with myocardial injury.

The study "suggests that although an elevated troponin level may be a marker of poor outcomes, other processes, including thrombosis, may also be important determinants of outcomes," the editorialists wrote.

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