The role of colchicine in the management of COVID-19: a Meta-analysis

Abstracts of articles identified using the search strategy above mentioned were viewed, and articles that appeared to fulfil the inclusion criteria were retrieved in full. Data on at least one of the outcome measures was included in the study. Each article identified was reviewed and categorized into one of the following groups: Included: Randomized and non-randomized clinical trials, and Cohort studies that met the described inclusion criteria and those where it was impossible to tell from the abstract, title or MESH headings. Excluded: review, opinion studies, case series, and studies conducted on animals. When there was a doubt, a second reviewer (MFA) assessed the article, and a consensus was reached. The literature was reviewed till May 31, 2022 and yielded 814 articles after ranking the articles according to authors and year of publication. Only articles fulfilling the inclusion criteria were included (total 8 articles) for further steps of data collection, analysis, and reporting. The studies that met our inclusion criteria were Deftereos et al., Tardif et al., RECOVERY Collaborative Group, Lopes et al., Sandhu et al., Mareev et al., Brunetti et al. and Scarsi et al. [20‐27]. All were in English and there were no available studies published in Arabic, French or Spanish language.

A copy of each identified paper was obtained, and relevant data was abstracted by the first reviewer for a quantitative overview. We extracted the following study data from full-text articles: first author name, year of publication, study design, study location, eligibility criteria, sample size, age, sex, description of intervention and control groups, primary and secondary outcomes. In case of discrepancies or when the information presented in a study was unclear, abstraction by a second reviewer (MFA) was sought to resolve the discrepancy.

Data were abstracted from every study in the form of a risk estimate and its 95% confidence interval. When a risk estimate and its 95% confidence interval were not available from the article, we calculated unadjusted values from the published data of the article, using the Epi Info 6 computer program version 6.04d.

Pooled estimates of relative risks were obtained by weighing each study by the inverse variance of the effect measure on a logarithmic scale. This approach to pool the results assumed that the study populations being compared were similar and hence corresponded to a fixed effect analysis. The validity of pooling the relative risks was tested (test of homogeneity) using chi square test.

A violation of this test suggested that the studies being pooled differed from one another. In the presence of significant heterogeneity of the effect measure among studies being compared, we performed a random effect analysis that was based on the method described by DerSimonian and Laird. The random effect analysis accounted for the interstudy variation. Because the test of homogeneity had low power, we reported the figures of the random effect analysis even with the absence of significant heterogeneity.

All statistical analyses for pooling the studies were performed on the MetaXL Software.

Two studies were cohort (Brunetti et al. and Scarsi et al.) while the other studies were four randomized controlled clinical trials (Deftereos et al., RECOVERY Collaborative Group, Lopes et al., and Tardif et al.) and two non-randomized controlled clinical trials (Mareev et al., and Sandhu et al.).

Two studies were multicentre clinical trials (RECOVERY Collaborative Group, and Tardif et al.). The other six studies were conducted in Greece (Deftereos et al.), Brazil (Lopes et al.), the USA (Brunetti et al. and Sandhu et al.), Russia (Mareev et al.), and Italy (Scarsi et al.) [22‐29].

The studies included both hospitalized and non-hospitalized COVID-19 patients, who were diagnosed either clinically or by laboratory diagnosis with PCR–RT testing and CT chest imaging (Table 1).

Table 2 and Fig. 2 showed that the meta-analysis of all included studies showed a significant difference in mortality between the treatment group with colchicine and the control group (RR 0.35, 95% CI: 0.15–0.79). There is significant heterogeneity among the studies (Homogeneity Test X2: 42.219, P-value < 0.000).

Table 3 shows the efficacy of colchicine on the duration of COVID-19 illness till recovery. Lopes et al. reported that the median duration of COVID-19 illness in the treatment group with colchicine was 7 days vs 9 days in the control group (P-value =0.003) [25]. While Sandhu et al., and Mareev et al., demonstrated that colchicine had no significant effect on the illness duration [26, 27]. (Table 3).

Tardif et al., reported that colchicine did not show a significant effect on the COVID-19 patients’ need for hospitalization RR 0.79, 95% CI 0.60–1.03, P-value =0.081) [23].

Lopes et al., demonstrated that colchicine use resulted in a significant decrease in the need for O2 therapy in patients with COVID-19 (RR 0.07, 95% CI 0.02–0.27, P = 0.000024) [25].

Table 4 and Fig. 3 show the efficacy of colchicine on need for ICU admission in patients with COVID-19. The meta-analytical result did not show a significant effect (RR 0.29, 95% CI: 0.07–1.17).

Table 5 and Fig. 4 show the efficacy of colchicine on need for artificial ventilation in patients with COVID-19. The meta-analysis of four studies demonstrated that colchicine has no significant effect on the need for artificial ventilation (RR 0.40, 95% CI 0.14–1.13). There is significant heterogeneity among the studies (Homogeneity Test X2: 18.417, P-value: 0.000).

Table 6 and Fig. 5 show the efficacy of colchicine on hospital discharge rate in patients with COVID-19. The meta-analytical result of the three studies demonstrated that colchicine did not show a significant effect on the hospital discharge rate (RR 0.99, 95%CI 0.12–7.85).

The effect of colchicine on the hospital discharge rate in the clinical trials was not significant (RR 0.98, 95%CI 0.12–8.02), while a cohort study reported that colchicine showed a significant effect on the hospital discharge rate (RR 5.0, 95%CI 1.25–20.08, P-value 0.023) [28].

Table 7 and Fig. 6 show the efficacy of colchicine on mortality among PCR confirmed COVID-19 Patients. Colchicine did not show a significant effect on mortality among PCR confirmed COVID-19 patients (RR 1.02, 95% CI 0.74–1.41).

The eight pooled studies evaluated the efficacy of colchicine on mortality among COVID-19 patients and showed a significant reduction in the mortality rate among patients received colchicine in comparison with placebo or standard care. This result coincides with the findings of a recent systematic review that reported a significant decrease in the all-cause mortality in three observational studies [28]. In addition, a recently published meta-analysis reported that colchicine resulted in decreased mortality among COVID-19 patients. This study pooled four randomized control trials and five observational studies and involved 5522 patients only [29].

On the other hand, Mehta, et al. and Toro-Huamanchumo, et al. documented that colchicine had no effect on the mortality rate among COVID-19 patients [30, 31].

The heterogeneity test between the pooled studies showed a significant difference, which indicates interstudy variation. Pooling of these heterogeneous studies added more useful information.

According to our result, colchicine may have a beneficial effect to decrease mortality among COVID-19 patients. It was obvious that this effect occurred when colchicine was used within the early days of the disease. These findings can be explained by the anti-inflammatory role of colchicine that is mediated through the interaction between colchicine and microtubules which play an important role in cellular division, migration, and adhesion. This effect robustly influences the immune system response and reduces the inflammatory reaction. Also, colchicine decreases the release of cytokines and inflammatory mediators that stimulate the immune cells [32].

The subgroup analysis of the two cohort studies demonstrated a significant effect of colchicine on mortality among COVID-19 patients. However, the subgroup analysis for the six clinical trials showed that colchicine has no effect on mortality in the management of COVID-19. This result is consistent with the pooled analysis of a recent study where four clinical trials only were included [33]. This variation could be attributed to difference of the study design, variation in follow up duration and the colchicine regimen used in these studies.

The efficacy of colchicine on the duration of COVID-19 illness was assessed in three clinical trials. Lopes et al. found that hospitalized COVID-19 patients who received colchicine had a shorter duration of illness till recovery in comparison with the patients who received placebo [23]. This is similar to the result reported by a recent study [34]. This finding can be related to the anti-inflammatory and immune modulatory roles of colchicine in the management of COVID-19. On the other hand, two clinical trials reported that colchicine did not affect the duration of COVID-19 illness [23, 25]. These findings agree with the results of a recently published study investigated the efficacy of colchicine on the duration of COVID-19 clinical course [31].

Tardif et al., investigated the efficacy of colchicine among non-hospitalized COVID-19 patients vs placebo. They found that colchicine did not influence the need for hospitalization among the non-hospitalized patients [21]. A recent clinical trial was conducted to assess the effect of colchicine on the prognosis of non-hospitalized COVID-19 patients and the results showed no significant effect of colchicine on hospitalization rate of the patients [35].

Lopes et al., assessed the efficacy of colchicine on the need for O2 therapy and the results demonstrated that colchicine use resulted in a significant decrease in the need for O2 therapy in patients with COVID-19 [23]. This result can be understood based on the beneficial effect of colchicine on the inflammatory response.

The pooled results of two clinical trials showed that colchicine did not improve the need of ICU admission compared to placebo or standard care. This finding is concomitant with a recent study that included six studies only [30].

Four pooled studies evaluated the efficacy of colchicine on need for artificial ventilation and showed that colchicine did not decrease the need for artificial ventilation compared to placebo or standard care [20‐22, 24].

The heterogeneity test between the pooled studies regarding the need for artificial ventilation showed a significant difference, which indicates interstudy variation.

This can be attributed to the variation of duration and dose of colchicine regimens in these studies, and the severity of the disease. Tardif et al., included non-hospitalized COVID-19 patients while the other three studies involved hospitalized patients.

Three pooled studies evaluated the efficacy of colchicine on hospital discharge rate and showed that colchicine did not improve the hospital discharge rate in comparison with placebo or standard treatment [22, 24, 26].

Furthermore, the subgroup analysis of the pooled results included two clinical trials and showed that colchicine did not cause a significant improvement in the hospital discharge rate compared to placebo or standard treatment [22, 24]. On the other hand, the cohort study demonstrated a beneficial effect of colchicine on the hospital discharge rate compared to standard care [26].

The variation of the results of the three studies could be attributed to the difference of study design, number of included patients, and the treatment regimens used.

Two pooled studies evaluated the efficacy of colchicine among PCR confirmed COVID-19 patients and showed that colchicine did not significantly decrease mortality among PCR confirmed patients [21, 22].

In addition, Tardif et al. assessed the efficacy of colchicine on hospitalization rate among PCR confirmed COVID-19 patients and found that colchicine significantly decreased the hospitalization rate compared to placebo. Also, Tardif et al. evaluated the effectiveness of colchicine on mechanical ventilation rate among PCR confirmed COVID-19 patients and showed no beneficial effect of colchicine on mechanical ventilation in comparison with placebo [21].