New insights into colchicine's disruption of the pathway that contributes to arterial inflammation and new clinical studies of the drug could pave the way toward greater use of the anti-inflammatory drug in patients with or at risk for atherosclerotic cardiovascular disease (ASCVD), researchers said at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.
Colchicine was approved by the US Food and Drug Administration in June 2023 in a once-daily 0.5-mg formulation under the brand name Lodoco to reduce the risk for major adverse cardiovascular events (MACE) in patients with established atherosclerotic disease or with multiple risk factors for CVD. The Lodoco formulation is slightly smaller than the 0.6-mg formulation that's taken twice daily for the prophylaxis and treatment of acute gout flares.
In a presentation at the conference, Binita Shah, MD, one of the principal investigators in trials of Lodoco, explained how the inflammatory pathway contributes to atherosclerosis and provided an update on how colchicine disrupts the pathway. Shah is an associate professor of medicine at New York University in New York City and director of research at NYU Langone Health Interventional Cardiology.
"Colchicine dampens inflammatory markers on neutrophils so that they are less likely to be attracted to inflamed or injured endothelium, which would be the site of where plaque is building up or where the plaque has ruptured in the setting of a heart attack," Shah told Medscape Medical News after her presentation.
The Inflammatory Pathway
Shah explained that normal coronary endothelium resists adhesion by circulating leukocytes, but inflamed or injured coronary endothelium attracts those neutrophils via two types of selectins: L-selectins on neutrophils and E-selectins on endothelial cells. Those neutrophils then release inflammatory cytokines including interleukin-1 beta (IL-1ß), which then triggers production of IL-6 and, subsequently, high-sensitivity C-reactive protein (hsCRP), which contributes to plaque formation, she said.
"Colchicine affects these pathways with a balance for safety and effect on clinical outcomes, particularly to reduce recurrent myocardial infarction [MI]," Shah said during her presentation.
Results from the CIRT demonstrated that methotrexate is ineffective in blocking the adenosine-mediated anti-inflammatory pathway, Shah said, so focusing on the IL-1ß–IL-6–hsCRP pathway, which is known to work based on the results of the CANTOS trial, could pay dividends.
"This is where colchicine can potentially play a role," she said.
Shah cited a secondary analysis of the CANTOS trial in which the magnitude of hsCRP reduction correlated with a reduction in MI, stroke, or cardiovascular death. The secondary analysis showed that patients who received canakinumab and achieved hsCRP ≥ 2 mg/L had a nonsignificant 5% lower risk and those who reached < 2 mg/L had a statistically significant 25% lower risk than those who received placebo.
The COPE-PCI Pilot trial demonstrated the benefit of targeting the interleukin pathways, she noted.
Further clarification of the role of colchicine in managing patients with acute coronary syndrome may come from two other randomized trials now underway, Shah said: POPCORN is evaluating colchicine to reduce MACE after noncardiac surgery, and CLEAR SYNERGY is evaluating the best timing for colchicine therapy after an acute MI.
Shah presented preliminary data from her group from a neutrophil biomarker substudy of CLEAR SYNERGY that isolated neutrophils from patients who had an acute MI. "We treated them with various doses of colchicine and showed that the interaction between those treated neutrophils [and] the endothelial cells were a lot lower; they were less sticky to endothelial cells as colchicine was administered," she said in her presentation. She added that colchicine also reduced neutrophil chemotaxis and neutrophil activation and potentially inhibited inflammasomes, decreasing IL-1ß production.
What's more, colchicine has been shown to not affect platelets alone but rather platelets at the site of inflammation or plaque rupture, Shah added. "At currently used doses, colchicine does not inhibit platelet activity [by] itself, so we've never seen increased bleeding events, but it will dampen neutrophils' ability to latch onto a platelet that could contribute to a clot," she told Medscape Medical News later.
"There are multiple studies, both retrospective studies in gout cohorts as well as prospective studies in the cardiovascular cohort, that all show consistently one thing, which is that colchicine continues to reduce the risk of having a recurrent MI in patients who either have cardiovascular disease or are at high risk of having cardiovascular disease," she told Medscape Medical News.
"I think that's very helpful to know that it's not just one study — it's not just a fluke, potentially a play of chance — but multiple studies consistently showing the same thing: That there's a reduced risk of acute MI."
Slow to Embrace Colchicine
Despite this evidence, cardiologists and rheumatologists have been slow to embrace colchicine for patients at risk for cardiovascular events, said Michael Garshick, MD, who attended the conference and is head of the Cardio-Rheumatology Program at NYU Langone. "What [Shah] really highlighted was that for a number of years now, we've had several clinical trials showing the benefit of low-dose colchicine to prevent atherosclerotic cardiovascular events, and yet despite these and that there's now an indication to use low-dose colchicine to reduce cardiovascular disease, we're still struggling for this medication to be taken up by the general cardiology community to treat high-risk patients.
"There's still some work to do to prove that we need to break those barriers," Garshick added. Some of the confusion surrounding the use of colchicine for ASCVD may be attributed to the 0.5-mg dose approved for CVD as opposed to the long-approved 0.6-mg dose for gout, he said. "People are generally confused: Is it OK to use the 0.6-mg dose?" Garshick said.
Potential gastrointestinal side effects may be another concerning factor, although, he added, "we didn't see any major complications." Another issue could be polypharmacy in many of these patients, he said.
Garshick concurred with Shah that the existing evidence supporting the use of colchicine to reduce risk for cardiovascular events is strong, but more will come out. "I think there's going to be evolving data supporting it," he said.
Shah disclosed financial relationships with Philips Volcano and Novo Nordisk. She is also a principal investigator of the CLEAR SYNERGY biomarker substudy and the POPCORN trial.
Garshick disclosed relationships with Kiniksa Pharmaceuticals, Agepha Pharma, Bristol Myers Squibb, and Horizon Therapeutics.
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