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Three Part Question

In [hospitalised adult patients with a confirmed diagnosis of COVID-19] does [colchicine administration] reduce [patient mortality]?

Clinical Scenario

You are the EM Specialist Trainee covering the resus room for respiratory patients. The 'red phone' rings to pre-alert the department about a 52 year old woman who tested positive for COVID-19 3 days ago. She is breathless with oxygen saturations of 74% on room air and will arrive in 5 minutes. During a recent conversation with a rheumatologist about a different patient, colchicine was mentioned as being currently under investigation for treatment of COVID-19 due to its well-known anti-inflammatory properties. You wonder if there is any evidence to suggest this potential treatment would be beneficial for your impending arrival...

Search Strategy

A search of the EMBASE, PubMed and Medline databases was conducted using the NICE Healthcare Advanced Databases Search interface.
Search terms were as follows:

"(colchicine AND (covid-19 OR covid OR coronavirus OR sars-cov-2)).ti,ab"

Search Outcome

140 papers were identified. After review of abstracts, 4 were deemed relevant to the clinical scenario. Of these, there was 1 RCT and 3 cohort studies. The papers are presented in Table 1.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Deftereos June 2020 Greece	105 patients with COVID-19 confirmed with PCR-reverse transcriptase testing. 50 patients received standard medical treatment as defined by local protocols. 55 patients received standard medical treatment plus colchicine until hospital discharge or for a maximum of 21 days.	Open-label, multi-centre RCT	Time to deterioration by 2 points on the WHO R&D Blueprint Ordinal Scale	14% (7 patients) reached the primary clinical end-point in the control group vs 1.8% (1 patient) in the colchicine group (Odds Ratio 0.11; 95%CI 0.01 - 0.96; p = 0.046)). Cumulative event-free 10-day survival was 83% in the control group vs 97% in the colchicine group (p = 0.03).	Sampling strategy not described so potential for selection bias. Study was under-recruited and subsequent small sample size is reflected in the wide confidence intervals. Unblinded study - given the primary clinical outcome depends partly on a subjective clinical decision to escalate care or not, there is potential for bias. 3 primary outcomes when there should only be one. Use of biochemical markers as primary outcome measures - this is not patient-centred. Trial sponsored by 3 pharmaceutical companies so potential conflict of interest.
			Maximum high-sensitivity cardiac troponin level	No significant difference between groups in median high sensitivity troponin level reached.
			Time to reach CRP > 3 x the upper reference limit	Not reported due to 68.6% of patients having surpassed the upper reference limit x 3 at baseline. However, the maximum CRP level reached in both groups was not statistically significantly different.
Brunetti September 2020 USA	303 consecutive hospitalized patients with COVID-19 confirmed by PCR testing, of which 41 received colchicine. After propensity score matched analysis using a-priori defined co-variates, 33 patients who received standard medical treatment were matched with 33 patients who received standard medical treatment plus colchicine.	Single-centre, propensity score matched, open-label, retrospective cohort study	In-hospital death within 28-days follow-up	11 deaths (33.3%) in control group vs 3 deaths (9.1%) in the colchicine group (Odds Ratio 0.20; 95%CI 0.05 - 0.80; p = 0.023).	Retrospective, observational, unblinded study prone to bias. Propensity matching unable to control for unknown confounders between groups. Small sample size resulting in wide confidence intervals. Colchicine treatment regimen varied between patients in intervention arm. Significantly more hydroxychloroquine and azithromycin use in control arm.
Scarsi June 2020 Italy	262 patients with virologically and radiographically confirmed COVID-19. 140 patients received standard medical treatment and compared with 122 patients who recieved standard medical treatment plus colchicine.	Single centre, open-label, retrospective cohort study	Survival Rate at 21 days of follow-up	63.6% (SE = 4.1%) in the control group vs 84.2% (SE 3.3%) in the colchicine group (p = 0.001).	Retrospective, observational, unblinded study prone to bias. Colchicine group had a significantly decreased rate of patients with underlying malignancies and a significantly increased concomitant use of corticosteroids - potential confounders of survival benefit detected. Delay in initiation of colchicine in patients in intervention arm may introduce bias - if they survived long enough for a delayed inclusion, it is possible this group contained patients more likely to survival at baseline regardless of the intervention.
Sandhu October 2020 USA	112 patients with COVID-19 confirmed with nasal swab PCR testing. 78 patients who received standard medical treatment were compared with 34 patients who received standard medical treatment plus colchicine.	Single centre, open label, prospective cohort study	Mortality rate	63 patients (80.8%) in control group vs 16 patients (47.1%) in the colchicine group.	No randomised allocation of patients - risk of selection bias. Unblinded study. Small sample size. Significantly lower percentage of patients in the colchicine group with hypertension, diabetes mellitus and renal failure - may contribute to survival benefit seen.
			Intubation rate	68 patients (87.2%) in control group vs 16 patients (47.1%) in the colchicine group.
			Discharge rate	15 patients (19.2%) in the control group vs 18 patients (52.9%) in the colchicine group.

Comment(s)

Colchicine, an alkaloid derived from the autumn crocus, is historically associated with the treatment of gout (or 'podagra', meaning 'foot seizure', when it affects the 1st metatarsophalangeal joint) and there is evidence it was used for this purpose by Byzantine physicians as early as the 5th Century AD. It has been proposed that the anti-inflammatory properties of colchicine may help to attenuate the 'cytokine storm' associated with SARS-CoV-2 infection. 3 observational studies have all reported a decrease in mortality associated with colchicine use in hospitalised patients with COVID-19 but data from these unblinded and non-randomised studies should be considered nothing more than hypothesis generating. The GRECCO-19 randomised controlled trial was able to demonstrate a statistically significant reduction in clinical deterioration for hospitalised patients treated with colchicine when compared to standard medical care but, due to the study weaknesses, it would be premature to consider this conclusive. There are numerous clinical trials currently registered with clinicaltrials.gov with the aim of investigating the impact of colchicine on coronavirus infection. If nothing else, it seems possible this future work has the potential to contribute to a body of evidence which breathes new life into the use of an old drug!

Clinical Bottom Line

Colchicine has potential to reduce mortality for adults hospitalised with COVID-19, but larger randomised studies with clinically relevant outcome measures are required before widespread use is adopted.

References

1. Deftereos SG, Giannopoulos G, Vrachatis DA 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 JAMA netwrok open Jun 2020; vol. 3 (no. 6); p. e2013136
2. Brunetti L, Diawara O, Tsai A et al. Colchicine to Weather the Cytokine Storm in Hospitalized Patients with COVID-19 J Clin Med. 2020 Sep 14;9(9):296
3. Scarsi M, Piantoni S, Colombo E et al. Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome Ann Rheum Dis. 2020 Oct;79(10):1286-1289
4. Sandhu T, Tieng A, Chilimuri S and Franchin G A Case Control Study to Evaluate the Impact of Colchicine on Patients Admitted to the Hospital with Moderate to Severe COVID-19 Infection Canadian Journal of Infectious Diseases and Medical Microbiology vol. 2020, Article ID 8865954, 9 pages, 2020