Colchicine to reduce CVD – is it prime time yet?

12th May 2024, A/Prof Chee L Khoo

ASCVD

We are used to using colchicine for acute treatment of gout but colchicine has also proven itself a key pharmacotherapy in the treatment of cardiovascular conditions such as pericardial disease (1), post-operative atrial fibrillation (2) and coronary artery disease (3). Colchicine disrupts the inflammatory response in acute gout but the inflammatory pathways that colchicine acts on are also found in other inflammatory diseases including coronary artery disease. 2023 marks a particularly important year for this drug within the CV sphere, with the FDA’s approval of colchicine 0.5 mg for reducing CV disease events in patients with established or high risk of atherosclerotic CVD (ASCVD). We need to see where colchicine fits into the management of our patients with ASCVD.

Gout is an inflammatory arthritis that is the result of the precipitation of serum urate into crystallised deposits of monosodium urate (MSU) in and around the joint. By understanding the mechanism of inflammation in gout and the action of colchicine in acute gout inform us on how colchicine may work in other inflammatory pathways. Patients who had suffer an acute gout attack will tell you how intense the pain and inflammation is.

Mechanisms in gouty arthritis

It is not surprising to learn that MSU triggers several concurrent inflammatory pathways resulting in the acute gout attack:

  1. MSU crystals interact with the surface of dendritic cells through crystal-lipid contact in a manner that does not rely on specific cell surface receptors. Lipid bilayer perturbation may trigger an intracellular signalling cascade, leading to spleen tyrosine kinase (Syk) activation and additional dendritic cell activation (4)
  2. MSU crystals bind to Toll-like receptors (TLRs). In the presence of myeloid differentiation factor88 (MyD88), nuclear factor-κB (NFκB) is induced and pro-inflammatory molecules are released. The expression of multiple adhesion molecules on the surface of endothelial cells is increased.
  3. MSU crystal phagocytosis leads to phago-lysosomal damage, which leads to potassium efflux. The addition of available reactive oxygen species (ROS), ASC and pro-caspase-1 to the nucleotide-binding domain leucine-rich repeat-containing 3 (NLR3) receptor forms the NLRP3-inflammasome complex, which induces interleukin 1β (IL-1β). ASC, apoptosis- associated speck-like protein containing a caspase recruitment domain; tumour necrosis factor (TNF).

You can see that uric acid triggers and activate a whole host of inflammatory cells (dendritic, myeloid, macrophages, monocytes, neutrophils), inflammatory cytokines (NLR3, IL-1β, TNF), endothelial surfaces changes and increase reactive oxygen species. Many of these mediators and changes are implicated in ASCVD.

Mechanisms of action of colchicine

Colchicine is known to work in acute gout by preventing microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. By disrupting the activation of NLRP3-inflammasome complex , colchicine prevents the processing of the interleukin (especially IL-1β) cascade. Colchicine also suppresses the production of the ROS which curtail the formation of NLRP3-inflammasome complex upstream. Importantly, colchicine also interferes with the adhesiveness of neutrophil by decreasing neutrophil L-secretin expression and E-secretin distribution on the surface of endothelial cells.

In addition to interfering with the actions of pro-inflammatory pathways, colchicine also increases levels of anti-inflammatory molecules that may contribute to clinical benefit in patients with gout. Colchicine is really a wonder drug with multiple mode of attack to dampen down the inflammation.

Colchicine in CVD reduction

Results from a large-scale medical-records review suggest that colchicine treatment may significantly decrease cardiovascular risk (5). In this study, the prevalence of myocardial infarction was significantly lower among colchicine users (P < 0.03), and there were numerically but not significantly lower mortality and CRP levels among those with a history of colchicine use. The investigators suggested that colchicine may support plaque stability and/or reduce the effects of plaque rupture and that these effects may have been due to blockade of macrophage activation, endothelial activation, and/or neutrophil influx.

In a prospective randomised observer blinded study, Nidorf et al explored whether low dose colchicine could prevent cardiovascular events in patients with clinically stable coronary disease (6). Patients were randomised to either receive 0.5mg colchicine or no colchicine in addition to standard therapy including aspirin and/or statins. Patients were followed up for a median of 3 years. The primary end point was the composite prevalence of acute coronary syndromes, out-of-hospital cardiac arrest and non-cardio embolic ischaemic stroke. Patients on colchicine reported a 5.3% primary outcome event vs 16.0% in the group not on colchicine.

The LoDoCo2 (Low-Dose Colchicine 2) trial was the main trial the FDA looked at when they approved low dose colchicine for reducing CV events (7). Tjerk SJ et al randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed.

In 5522 randomised patients, colchicine consistently reduced the primary endpoint in patients with no prior ACS (hazard ratio [HR]: 0.81), recent ACS ( HR: 0.75), remote ACS (HR: 0.55) and very remote ACS (HR: 0.70). In other words, the benefits of colchicine were consistent irrespective of history and timing of prior ACS.

In summary, there is increasing evidence to support the use of colchicine in treating cardiovascular disease. Colchicine is used as a CVD treatment and not as a gout treatment. Uric acid levels in these patients were not even mentioned in the studies. In the LoDoCo2 trial, low dose colchicine used was 0.5mg colchicine under the proprietary brand, LoDoCo. In the US, the approved dose for prophylaxis and treatment of acute gout is 0.6 mg. This might be a factor why physicians may be slow to embrace the use of colchicine in patients at risk of CV events. We have no such confusion here in Australia as colchicine comes in 0.5mg. We should be asking why isn’t this patient with known CVD or at high risk of CVD on low dose colchicine.

References:

  1. G. Lazaros, M. Imazio, A. Brucato, et al. The role of colchicine in pericardial syndromes Curr Pharm Des, 24 (6) (2018), pp. 702-709
  2. J.Z. Lee, S. Nirmal, C.L. Howe, et al. Colchicine for prevention of post-operative atrial fibrillation JACC Clin Electrophysiol, 2 (1) (2016), pp. 78-85
  3. T. Kofler, R. Kurmann, D. Lehnick, et al. Colchicine in patients with coronary artery disease: a systematic review and meta-analysis of randomized trials J Am Heart Assoc, 10 (16) (2021), Article e021198
  4. Ng G, Sharma K, Ward SM, et al. Receptor-independent, direct membrane binding leads to cell-surface lipids or tingand Syk kinase activation in dendritic cells. Immunity. 2008;29:807–818.
  5. Crittenden DB, Lehmann RA, Schneck L, et al. Colchicineuseis  associated with decreased prevalence of myocardial infarction in patients with gout. J Rheumatol. 2012;39:1458–1464.
  6. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404–410.
  7. Tjerk SJ et al. Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome, Journal of the American College of Cardiology, Volume 78, Issue 9, 2021,