Colchicine for the prevention of COVID-19 “hard” outcomes: All that glitters is not gold

Published:November 24, 2021DOI:https://doi.org/10.1016/j.ejim.2021.11.016
      Dear Editor,
      In a paper recently published in the European Journal of Internal Medicine, Schattner provided a thorough and in-depth review regarding the multiple, pleiotropic effects of colchicine, also highlighting its potential beneficial effects in coronavirus disease 2019 (COVID-19) [
      • Schattner A.
      Colchicine-new horizons for an ancient drug.
      ]. In their commentary, Kow et al. [
      • Kow Siang C.
      • Sangarran Ramachandram D.
      • Shahzad Hasan S.
      Colchicine for COVID-19: hype or hope?.
      ] emphasize on the need for further trials with a longer treatment duration for the assessment of colchicine's therapeutic efficacy, dampening the initial enthusiasm. Previous meta-analyses of observational studies and randomized controlled trials demonstrated a mortality benefit with colchicine in patients with COVID-19, leading to the amendment of treatment protocols against the disease worldwide [
      • Nawangsih E.N.
      • Kusmala Y.Y.
      • Rakhmat I.I.
      • et al.
      Colchicine and mortality in patients with coronavirus disease 2019 (COVID-19) pneumonia: a systematic review, meta-analysis, and meta-regression.
      ,
      • Elshafei M.N.
      • El-Bardissy A.
      • Khalil A.
      • et al.
      Colchicine use might be associated with lower mortality in COVID-19 patients: a meta-analysis.
      ].
      Upon the recent publication of further randomized controlled trials, we sought to determine whether colchicine compared to standard of care offers a true benefit, both in the in-hospital and out of hospital setting, for the prevention of surrogate COVID-19 outcomes. We searched PubMed and Cochrane Library databases for relevant published randomized controlled trials up to 12th November 2021. We set as primary efficacy outcome the surrogate endpoint of COVID-19 death and as secondary efficacy outcome that of mechanical ventilation. We extracted the data from the eligible reports, by using a pilot tested, data extraction form.
      As we assessed only dichotomous variables, differences were calculated with the use of risk ratios (RR), with 95% confidence interval (CI), after implementation of the Mantel-Haenszel (M-H) random effects formula. Statistical heterogeneity among studies was assessed by using I2 statistics. All analyses were performed at the 0.05 significance level, while they were undertaken with RevMan 5.3 software.
      We finally included 6 randomized controlled trials [
      RECOVERY Collaborative Group
      Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial [published online ahead of print, 2021 Oct 18].
      ,
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: the GRECCO-19 Randomized Clinical Trial.
      ,
      • Lopes M.I.
      • Bonjorno L.P.
      • Giannini M.C.
      • et al.
      Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
      ,
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ,
      • Pascual-Figal D.A.
      • Roura-Piloto A.E.
      • Moral-Escudero E.
      • et al.
      Colchicine in Recently Hospitalized Patients with COVID-19: a Randomized Controlled Trial (COL-COVID).
      ,
      • Mareev V.Y.
      • Orlova Y.A.
      • Plisyk A.G.
      • et al.
      Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study.
      ] in at total of 15,624 subjects with documented COVID-19 infection. All trials except for one [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ] enrolled hospitalized patients. As shown in Fig. 1, colchicine was not superior to standard of care in terms of prevention of COVID-19 death (RR = 0.63, 95% CI; 0.33 – 1.20, I2 = 28%). In addition, colchicine did not result in a significant decrease in the risk for mechanical ventilation during disease course (RR = 0.66, 95% CI; 0.36 – 1.20, I2 = 48%), as shown in Fig. 2.
      Fig. 1
      Fig. 1Effect of colchicine compared to control on the risk for COVID-19 death.
      Fig. 2
      Fig. 2Effect of colchicine compared to control on the risk for mechanical ventilation due to COVID-19.
      The present pooled analysis of relevant, published randomized controlled trials so far does not support the routine use of colchicine for the prevention of surrogate COVID-19 outcomes in daily clinical practice, either in the in-hospital or in the community therapeutic management of patients with COVID-19. Whether colchicine can positively affect the prognosis of COVID-19 in specific patients’ populations, such as those suffering from autoinflammatory diseases [
      • Nas K.
      • Eryilmaz N.
      • Geyik M.F.
      • Altaş A.
      COVID-19 in patients with familial Mediterranean fever treated with colchicine: case based review.
      ], has to be further confirmed in randomized controlled trials, besides hypothesis-generating observational studies.

      Funding

      None.

      Acknowledgments

      None.

      Declaration of Competing Interest

      None declared.

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