Colchicine Stabilizes Plaque in ACS Patients, Imaging Study Suggests

Adding colchicine to optimal medical therapy in patients with a recent acute coronary syndrome not only reduces inflammation as measured by high-sensitivity C-reactive protein (hsCRP) but also results in greater coronary plaque stabilization compared with medical therapy alone, according to the results of a new study.

Treatment with colchicine, an anti-inflammatory originally derived from the autumn crocus (Colchicum autumnale) that’s used in the treatment of gout and pericarditis, was associated with a significant reduction in low attenuation plaque volume (LAPV), which represents the necrotic core volume and is a marker of plaque instability.

There was a moderate positive correlation between the change in LDL cholesterol and LAPV, which suggests LDL might have contributed to plaque stabilization. However, LDL cholesterol levels were reduced in both groups.

For this reason, “improvements in plaque morphology are not driven solely by changes in LDL, but also by the anti-inflammatory properties of colchicine,” according to lead investigator Kaivan Vaidya, MBBS (Royal Prince Alfred Hospital, New South Wales, Australia), and colleagues. “This is supported by the substantially larger reduction in hsCRP in the treatment group compared to controls.”

Subodh Verma, MD (St. Michael’s Hospital, Toronto, Canada), who was not involved in the study but who has investigated the role of inflammation in cardiovascular disease, called colchicine a “pan-anti-inflammatory agent,” one that interrupts the interleukin-1β (IL-1β) and interleukin-6 (IL-6) signaling pathways. IL-1β is a cytokine involved in vascular inflammation and atherothrombosis.

“As expected, colchicine is showing its anti-inflammatory prowess in that CRP levels are going down and that is proof that it’s targeting and reducing inflammation,” Verma told TCTMD. “There’s been lots of interest in colchicine in terms of clinical trials, and prospective studies are ongoing.”

Recently, the CANTOS trial confirmed that treating inflammation can significantly impact cardiovascular event rates. In CANTOS, which included patients with a previous MI and elevated hsCRP levels, treatment with canakinumab (Novartis) reduced the relative risk of nonfatal MI, nonfatal stroke, or cardiovascular death—the study’s primary composite endpoint—by 15% when compared with placebo. Canakinumab is a fully human monoclonal antibody that inhibits IL-1β, which leads to a reduction in IL-6 and hsCRP levels.   

“The inflammation story that started many, many years ago in terms of it simply being an associative observation has now really been taken to the next level to show that inflammation is in fact a potential target for therapy,” said Verma. “CANTOS has helped in that regard in a big way.”

Plaque Biology ‘Affected in a Positive Way’

In the colchicine study, which was published October 18, 2017, in JACC: Cardiovascular Imaging, the Australian researchers treated 40 ACS patients with optimal medical therapy (including high-intensity statins to achieve LDL cholesterol levels less than 70 mg/dL) and 40 patients with optimal medical therapy plus colchicine 0.5 mg/day. The mean duration of follow-up was 12.6 months.

Colchicine was associated with a significant reduction in LAPV on coronary CT angiography compared with the control group (mean reduction 15.9 mm3 vs 6.6 mm3), as well as a significant reduction in hsCRP (mean reduction 1.10 mg/L vs 0.38 mg/L). The reduction in total atheroma volume was similar between the control and treatment groups. In multivariate analysis, colchicine remained associated with larger reductions in LAPV and hsCRP compared with what was seen in the control arm.

“Now we have intermediate confirmation from this important study showing that plaque biology is being affected in a positive way, in a way that would suggest reduced vulnerability and rupture risk,” Verma told TCTMD. “I think it’s very tantalizing information.”

In an editorial, Paul Ridker, MD (Brigham and Women’s Hospital, Boston, MA), who led the CANTOS study, and Jagat Narula, MD (Icahn School of Medicine at Mount Sinai, New York, NY), called the colchicine results “provocative” given that LAPV is considered an imaging marker for plaque instability and a predictor of adverse cardiovascular events.

Still, they cautioned against reading too much into the findings given the use of surrogate endpoints.

“Although imaging-verified change in the plaque composition (including LAPV or inflammation) should be intuitively more informative than the interval change in percent atheroma volume in response to therapeutic intervention, it is likely that no imaging modality would succeed as a validated surrogate for hard clinical events,” they write.

COLCOT, a 4,500-patient cardiovascular outcomes study with colchicine led by researchers from the Montreal Heart Institute, is currently ongoing, as is the Australian LoDoCo2 trial in patients with stable coronary disease. Verma said their research group is looking to launch a study investigating colchicine in peripheral artery disease patients.

In addition to colchicine, the anti-inflammatory agent methotrexate has also garnered significant interest. That drug is currently being tested in the 7,000-patient CIRT study led by Ridker and researchers at the Brigham and Women’s Hospital.

Until those cardiovascular endpoint trials are completed, however, there is a need to move slowly with colchicine and methotrexate, according to Ridker.

“There needs to be considerable caution in this field,” he told TCTMD via email. “All we know for certain is that canakinumab reduces hsCRP and cardiovascular event rates in the absence of lipid lowering. Until the ongoing trials of low-dose methotrexate and colchicine are done, we will have no way of knowing if alternative anti-inflammatory treatments benefit or harm our patients.”