Colchicine is unique in that its mechanism of action does not involve the arachidonic acid pathway, which is affected by non-steroidal anti-inflammatory drugs and glucocorticosteroids. Colchicine irreversibly intercalates into free α/β-tubulin dimers that incorporate into and block microtubule extension [18]. During inflammation, microtubules facilitate the movement of adhesion molecules onto cell surfaces. Colchicine concentrations are much higher in neutrophils than in other leukocytes due to the diminished activity of the P-glycoprotein membrane efflux pump, which serves as an energy-dependent colchicine efflux transporter [19]. Thus, even at low doses, it impairs adhesion of neutrophils to the endothelium by reducing both E- and P-selectin expression, inhibiting neutrophil migration, and thereby attenuating inflammation [20]. The disruption of microtubules also diminishes the rheologic capacity of neutrophils, inhibiting their transmigration out of blood vessels [21]. Although the mechanisms are less well understood, colchicine interferes with several steps in the inflammatory process by inhibiting the synthesis of TNF-α, leukotriene B4, prostaglandin E2 and TxA2, as well as the activity of cyclooxygenase-2 [22]. It also inhibits neutrophil release of α-defensin and diminishes neutrophil-to-platelet aggregation, thereby potentially preventing large thrombus burdens [23].

The innate immune response relies on pattern-recognition receptors to target pathogenic or dangerous signals. Inflammasomes are cytoplasmic pattern-recognition receptors, of which the best characterized is NLRP3 [24]. Colchicine has recently been shown to decrease IL-1β and IL-18 production by blocking the activity of the NLRP3 inflammasome. Two studies confirmed the inhibitory activity of colchicine at the NLRP3 inflammasome. In patients with ACS, in whom acute colchicine administration (1 mg followed by 0.5 mg within 24 hours before sampling) resulted in a significantly lower transcoronary release of these cytokines. The transcoronary cytokine levels of ACS colchicine-treated patients were notably similar to those of patients with no obstructive CAD [25]. The local reduction in IL-1β and IL-18 levels were highly suggestive of NLRP3 inflammasome inhibition. This was later confirmed in a follow-up study using stimulated peripheral monocytes from patients from a different cohort with ACS, where short-term colchicine administration resulted in a significant reduction of both intracellular and secreted IL-1β, via inhibition of inflammasome caspase-1 [26]. There are several mechanisms of action by which colchicine can suppress NLRP3 inflammasome activation: (1) inhibition of the expression of the pyrin domain, (2) prevention of intracellular transport of mitochondrial-associated apoptosis-associated speck-like protein containing a caspase recruitment domain to NLRP3, (3) inhibition of protein expression of cleaved caspase-1, and (4) inhibition of P2X7-mediated K⁺ efflux. The final process is the inhibition of the active form of IL-1β and IL-18 production and the recruitment of additional neutrophils and macrophages [8].

There has been recent interest in using low-dose colchicine to treat the chronic inflammation associated with atherosclerotic disease. The reduction in inflammatory biomarkers seems to be related to atherosclerotic plaque modification into a more stable phenotype. In a prospective, non-randomized study of 80 patients with recent ACS, 0.4 mg of colchicine daily plus optimal medical therapy resulted in a significant reduction of low-attenuation plaque volume seen on computed tomography coronary angiography (15.9 mm³ [–40.9%] vs. 6.6 mm³ [–17.0%]; P=0.008) and high-sensitivity C-reactive protein (mean, 1.10 mg/L [–37.3%] vs. 0.38 mg/L [–14.6%]; P<0.001). This change in low-attenuation plaque was positively associated with a reduction in high-sensitivity C-reactive protein levels in patients receiving colchicine (r=0.578, P<0.001) [27]. These favorable effects seem to be correlated with clinical benefits. In a retrospective study of 1288 gout patients, the prevalence of MI was 1.2% in colchicine users versus 2.6% in no-colchicine users (P=0.03). Colchicine users also had fewer deaths and lower C-reactive protein levels, although these did not achieve statistical significance [28]. According to a Cochrane meta-analysis including 39 randomized controlled trials with 4,992 patients receiving colchicine for multiple indications, colchicine may have substantial CV benefits, especially for the reduction of CV mortality and MI [29].

Colchicine’s activity in atherosclerosis was first examined in stable CAD. Colchicine (0.5 mg twice daily) was associated with a 60% relative reduction in C-reactive protein levels in patients with stable CAD on high-intensity atorvastatin therapy at baseline. This suggests that colchicine may have additive effects to statin therapy for reducing C-reactive protein levels [30]. In an earlier open-label trial of low-dose colchicine (LoDoCo) involving 532 patients with chronic CAD, treatment with colchicine (0.5 mg daily) was associated with a 67% relative risk reduction in acute CV events over 3 years, suggesting a potential role of colchicine on plaque stabilization [31]. A subsequent randomized double-blind trial involving 5,522 patients with chronic CAD after at least 6 months of a clinically stable condition (LoDoCo2) showed that low-dose colchicine prevented acute CV events, including CV death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization, which occurred at a 31% lower rate than in those who received placebo [32].

ACS is associated with higher risks of recurrent events and exacerbated inflammation. In a randomized double-blind trial involving 4,745 patients within a month after MI (Colchicine Cardiovascular Outcomes Trial [COLCOT]), the risk of acute CV events was also 23% lower in those who received low-dose colchicine (0.5 mg once daily) than those who received placebo. This result was due predominantly to a lower incidence of strokes and urgent hospitalizations for angina leading to coronary revascularization [33]. These benefits of colchicine with regards to CV events in COLCOT were at least as large as those of canakinumab in CANTOS.

However, there were no benefits in the Australian COPS (Colchicine in Patients With Acute Coronary Syndrome) Trial regarding the composite endpoint of all-cause mortality, ACS, ischemia-driven urgent revascularization, or non-cardioembolic ischemic stroke in 396 patients, who were randomized to colchicine (0.5 mg twice daily) for 30 days followed by 11 months of colchicine at a dose of 0.5 mg daily, compared with 399 patients randomized to placebo. There was a higher rate of total death (8 vs. 1; P=0.017, log-rank), particularly non-CV death, in the colchicine group (5 vs. 0; P=0.024, log-rank). However, this trial was underpowered to detect between-group differences with such a low event rate, and therefore these results must be interpreted with caution [34].

After ST-elevation MI (STEMI), an important inflammatory response starts in the minutes after reperfusion and peaks in the first days after reperfusion. Over the past years, a substantial volume of evidence has identified that inflammatory cells such as neutrophils, followed by monocytes and macrophages, rapidly infiltrate the injured myocardium with abundant proinflammatory cytokine secretions that may cause additional damage to the myocardium in patients presenting with STEMI [4,35].

Deftereos et al. [36] conducted a double-blind, placebo-controlled trial to determine whether a 5-day course of colchicine could reduce infarct size in 151 STEMI patients after percutaneous coronary intervention. Infarct size was measured by the surrogate endpoints of CK-MB fraction concentration and troponin T. Cardiac magnetic resonance imaging (MRI) with late gadolinium enhancement was used in a subset of 60 patients to measure infarct volume. Patients were randomized 1:1 to colchicine with a 2-mg loading dose followed by 0.5 mg twice daily or to placebo for 5 days. The 72-hour median area under the curve of CK-MB and peak troponin T was significantly reduced in patients receiving colchicine compared with placebo. There was a significant reduction in infarct volume as seen on cardiac MRI (median, 18.8 mL; interquartile range, 8.1–28.5 mL vs. median, 25.1 mL; interquartile range, 20.0–35.9 mL; P=0.019).

On the contrary, the COVERT-MI investigators randomly assigned 192 STEMI patients referred for primary percutaneous coronary intervention to receive oral colchicine (2-mg loading dose followed by 0.5 mg twice a day, n=101) or matching placebo (n=91) from admission to day 5. At 5 days, the gadolinium enhancement-defined infarct size did not differ significantly between the colchicine and placebo groups (P=0.87). At 3 months of follow-up, there were no significant differences in infarct size and left ventricular remodeling between the colchicine and placebo groups [37]. This discrepancy between these studies may be related to differences in study design. This former study assessed infarct size reduction by using myocardial biomarker release and only reported infarct size reduction on cardiac MRI in a subgroup of patients. The latter trial used an accepted primary endpoint with core laboratory measurement of cardiac MRI infarct size.

Inflammation has long been suggested to contribute to cardiac remodeling through crosstalk of inflammatory mediators, leading to chronic heart failure (CHF) by fibrosis, enhanced apoptosis, and cellular dysfunction. This has led to a number of clinical studies studying the potential of anti-inflammatory and immunomodulatory agents to influence the course of CHF. In a placebo-controlled trial of anakinra (an IL-1 receptor antagonist) in patients with MI, a 14-day course of anakinra treatment showed a beneficial effect on left ventricular end-systolic volume index compared to patients given a placebo, which is likely to have been due to a reduction in cardiac remodeling that takes place after the loss of viable heart muscle, resulting in CHF [38,39].

In contrast, Deftereos et al. [40] studied colchicine, an agent with known potent anti-inflammatory action, in 267 patients with stable symptomatic heart failure and systolic left ventricular dysfunction (ejection fraction ≤40%). This prospective, randomized study showed that a 6-month course of colchicine (0.5 mg twice daily) in patients with stable CHF, although effective in reducing inflammation biomarker levels, did not lead to any significant New York Heart Association functional improvement (odds ratio, 1.40; 95% confidence interval, 0.67–2.93; P=0.365) or affect the likelihood of death or hospital stay for heart failure (P=0.839). There is no doubt that colchicine can indeed suppress proinflammatory activation in patients with CHF, but this effect does not appear to lead to any discernible clinical benefits.